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CD4+ cells or helper T cells are produced in Thymus. How long these cells live? For example, RBC live for 3-4 months.
I will respond with a "story-like" approach. You may already know some info but I want to be sure I can help you fully understand!
Unlike RBC, you are born with all the CD4+ (or Th, as I refer to them) you will ever need in your lifetime in the primary organs of the immune system -- they are already specialized and ready to be used, and this has taken place in the thymus. On the other hand, RBC get renewed through erythropoiesis every ~120 days.
In utero, the thymus and bone marrow (primary organs) now supply secondary organs (lymph nodes, the spleen, the MALT) with the various cells they've made (B&T). However, only 5% leave the thymus, as 95% are recognized as "anti-self" and are killed. So this would be the first "killing" of Th cells. B cells live in the peripheral layer, while T cells live in the deep lymphoid tissue and the lymphoid dullet.
The dendritic cell will "wander" into the lymph node, carrying the fragment of antigen presentation on the MHC class 2 molecule-Dendritic cell resides between the B cell area and the T cell area. Now, the first specific thing occurs in the immune response, when the T cell receptor attaches to the antigen and tells cell says to make antibodies.
Now -- as of here, we have a lot of Th (and B) cells doing nothing while the antibody is being produced. Some of the Th will be killed, while some will serve as "memory Th cells" so that the next time such an antigen is present in your body, the response will be quicker. At this point, it's hard to distinguish which Th cells are dividing, and which are dying. The average lifespan has been reported to be >17 years. Source: https://www.ncbi.nlm.nih.gov/pubmed/24492253
I hope I have been able to help.
The life (and death) of CD4+ CD28(null) T cells in inflammatory diseases
Inflammation contributes to the development and perpetuation of several disorders and T lymphocytes orchestrate the inflammatory immune response. Although the role of T cells in inflammation is widely recognized, specific therapies that tackle inflammatory networks in disease are yet to be developed. CD4(+) CD28(null) T cells are a unique subset of helper T lymphocytes that recently shot back into the limelight as potential catalysts of inflammation in several inflammatory disorders such as autoimmunity, atherosclerosis and chronic viral infections. In contrast to conventional helper T cells, CD4(+) CD28(null) T cells have an inbuilt ability to release inflammatory cytokines and cytotoxic molecules that can damage tissues and amplify inflammatory pathways. It comes as no surprise that patients who have high numbers of these cells have more severe disease and poor prognosis. In this review, I provide an overview on the latest advances in the biology of CD4(+) CD28(null) T cells. Understanding the complex functions and dynamics of CD4(+) CD28(null) T cells may open new avenues for therapeutic intervention to prevent progression of inflammatory diseases.
Keywords: CD4+CD28null T lymphocytes apoptosis atherosclerosis autoimmunity co-stimulation helper T cells inflammation.
© 2015 John Wiley & Sons Ltd.
Characteristics of CD4 + CD28…
Characteristics of CD4 + CD28 null T cells in atherosclerosis. In patients that…
Regulatory T cells (Tregs) are a suppressive subset of CD4 + T helper (Th) cells important for the regulation of immune responses. The best-characterized Tregs are defined by expression of the transcription factor forkhead box protein 3 (FOXP3) and demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 locus. Demethylation of this element is thought to be crucial to maintain the stable, high expression of FOXP3 necessary for lineage stability and suppressive function (1, 2). Additional Treg markers include constitutive expression of the high-affinity IL-2Rα chain (CD25) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (3), along with low expression of the IL-7Rα chain (CD127) (4, 5). CD4 + CD25 + FOXP3 + Tregs can be divided into two main types: thymically derived Tregs (tTregs) and peripherally derived Tregs (pTregs) (6). Although it is difficult to distinguish between tTregs and pTregs phenotypically, both are thought to have an essential role in immune regulation (7).
Because of their immunoregulatory function, Tregs are an attractive therapeutic target in many different immune-mediated diseases, including transplantation, autoimmunity, and autoinflammation (8). An emerging concept is that Tregs are functionally specialized to their local environments (9), with the local milieu of cytokines, metabolites, and catabolites having major effects on the phenotype and function of these cells. In this review, we discuss current knowledge on how environmental factors affect Treg development, maintenance, and function, focusing on key recent findings in the area of cytokines, metabolites, and the microbiome.
How does a person's T cell count indicate AIDS?
HIV destroys CD4 T lymphocytes (helper T cells). Because of this, healthcare professionals measure CD4 levels to monitor HIV progression and AIDS.
Helper T cells are crucial for immune system function and activate after encountering antigens from disease-causing microorganisms. Antigens are biological markers that identify microorganisms such as bacteria and viruses.
When a CD4 count falls below a certain level, a person receives an AIDS diagnosis. The treatment a healthcare professional suggests depends on how low the CD4 count is.
Keep reading to learn more about T cells and their function and the link between T cell level and HIV and AIDS.
T cells grow from stem cells in the bone marrow. They are a type of white blood cell. There are two main types of T cells: helper T cells and killer T cells. Ultimately, it is the killer T cells that attack and kill cells that pathogens have infected.
Helper T cells
Macrophages are another type of white blood cell. They consume disease-causing microorganisms, or pathogens, then present fragments of their antigens to helper T cells. When a helper T cell binds to the antigen fragment that it recognizes, it activates and alerts other white blood cells to the pathogen.
Helper T cells have CD4 proteins on their cell surface, which help them bind to antigen fragments. Because HIV destroys helper T cells, healthcare professionals use a CD4 count to measure CD4 levels and HIV progression.
Killer T cells
After receiving the alert, killer T cells seek out and destroy the pathogen (virus, bacteria, or disease-causing microorganisms). Other white blood cells, such as B lymphocytes, will also activate and produce antibodies in order to protect against the threat.
HIV enters its genetic information into helper T cells to make copies of itself. When this happens, the helper T cells die. This severely disrupts the immune response. Low levels of helper T cells mean killer T cells and other white blood cells do not receive as much information about pathogens in the body. As a result, disease-causing bacteria and viruses multiply with minimal detection.
When the amount of helper T cells falls below 200 cells/mm 3 (cells per cubic millimeter), a person may receive an AIDS diagnosis. But healthcare professionals will also take into account other variables such as overall white blood cell count and the percentage of lymphocytes.
AIDS is the most severe stage of HIV. When a person receives an AIDS diagnosis, their immune system is severely compromised, and they are at risk for opportunistic illnesses. The survival rate without treatment at this stage is typically 3 years .
CD4 T cells are helper T cells. They express, or manifest, a CD4 protein on their cell surface that helps them bind to antigen fragments. These antigen fragments belong to viruses, bacteria, and other microorganisms that could threaten a person’s health. Killer T cells express a CD8 protein on their cell surface.
When activated, helper T cells mobilize other white blood cells to initiate a full immune response. Killer T cells, for example, then seek out the pathogen and destroy it by releasing granzymes, which trigger cell death.
If someone’s helper T cells are below 200 cells/mm 3 , they will likely receive an AIDS diagnosis.
When a person has HIV, a healthcare professional will collect a blood sample and request a CD4 count. The CD4 count helps determine how many helper T cells a person has.
But when analyzing a CD4 count, healthcare professionals must take into account that:
- CD4 levels could be lower in the morning and fatigue may affect CD4 levels
- corticosteroid levels could increase or decrease CD4 levels
All people whose helper T cells are below 200 cells/mm 3 should receive a CD4 count every 3–6 months. If treatment is working, a person may only need a CD4 checkup every 6–12 months.
The CD4 count helps healthcare professionals monitor HIV progression and if the person is at risk for opportunistic illnesses.
When a healthcare professional wants a CD4 count, they take a blood sample from a person’s arm.
Side effects of drawing blood may include:
A healthcare professional will likely only need to draw a small amount of blood, so a person should not feel any significant side effects.
Usually, when someone receives an HIV diagnosis, they will start antiretroviral therapy (ART) as soon as possible .
If a person responds well to ART, their CD4 levels may increase by 100–150cells/mm 3 after 1 year.
After analyzing a CD4 count, a healthcare professional can determine if the current care plan is working or if they need to introduce additional treatments.
As soon as CD4 levels drop below 200 cells/mm 3 , a healthcare professional may need to increase ART and administer other drugs to help bolster the immune system against opportunistic illnesses.
All people with HIV should receive a CD4 count every 3–6 months if their CD4 levels are below 200 cells/mm 3 , as this indicates a progression to AIDS. If the treatment is working and the CD4 count is stable, a person may only need a checkup every 6–12 months.
If a person receives an HIV diagnosis in time and starts ART promptly , it is unlikely their condition will progress to AIDS.
Taking ART not only keeps the volume of helper T cells high but also decreases the viral load (the amount of virus in the body).
If someone’s viral load decreases, it may reach an undetectable level. This means if a person keeps up the treatment for their condition, the virus cannot transmit to anyone through sex. Having an undetectable viral load also reduces HIV transmission during birth.
A healthcare professional requests a CD4 count to monitor helper T cell levels. When a person’s CD4 levels drop below 200 cells/mm 3 , the healthcare professional may diagnose that person with AIDS. If someone begins ART promptly after receiving an HIV diagnosis, their condition may never progress to AIDS.
T cells include two main types: helper T cells and killer T cells. Helper T cells express a CD4 protein on their cell surface that helps them bind to antigen fragments. These antigen fragments belong to disease-causing viruses and bacteria. After binding, the helper T cells signal other white blood cells to destroy the pathogen. Killer T cells are another type of T cell that break down pathogens by releasing granzymes that trigger cell death.
Corti, D. & Lanzavecchia, A. Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31, 705–742 (2013).
Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).
Jacobson, E. B., Caporale, L. H. & Thorbecke, G. J. Effect of thymus cell injections on germinal center formation in lymphoid tissues of nude (thymusless) mice. Cell. Immunol. 13, 416–430 (1974).
Mitchison, N. A. T-Cell–B-cell cooperation. Nat. Rev. Immunol. 4, 308–312 (2004).
Forster, R., Emrich, T., Kremmer, E. & Lipp, M. Expression of the G-protein–coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood 84, 830–840 (1994).
Forster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).
Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).
Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).
Campbell, D. J., Kim, C. H. & Butcher, E. C. Separable effector T cell populations specialized for B cell help or tissue inflammation. Nat. Immunol. 2, 876–881 (2001). The first in vivo characterization of helper T cells specialized in promoting the B cell response.
Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004).
Kim, C. H. et al. Unique gene expression program of human germinal center T helper cells. Blood 104, 1952–1960 (2004).
Haynes, N. M. et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J. Immunol. 179, 5099–5108 (2007). The first study to correlate a PD1 hi phenotype of activated T H cells with GC localization in the lymphoid tissue during a primary response.
Akiba, H. et al. The role of ICOS in the CXCR5 + follicular B helper T cell maintenance in vivo. J. Immunol. 175, 2340–2348 (2005).
Dorfman, D. M., Brown, J. A., Shahsafaei, A. & Freeman, G. J. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30, 802–810 (2006).
Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008). The first study to probe a genetic requirement for T FH cell development using a large suite of mutant mice, providing the initial evidence that T FH cells are independent of T H 1, T H 2, or T H 17 cell development and require ICOSL expression by the B cell compartment.
Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009). This study, together with references 17 and 18, establish that BCL-6 is required for T FH cell development.
Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009). See note to reference 16. In addition, this study reveals a striking antagonism between BCL-6 and BLIMP1 in regulating T FH cell development.
Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009). See note to reference 16. In addition, this study provides the most rigorous evidence that BCL-6 is required for T FH cell development in a T cell-intrinsic and gene dose-dependent manner.
Crotty, S. Follicular Helper CD4 T Cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).
Dodge, I. L., Carr, M. W., Cernadas, M. & Brenner, M. B. IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. J. Immunol. 170, 4457–4464 (2003).
Suto, A. et al. Development and characterization of IL-21-producing CD4 + T cells. J. Exp. Med. 205, 1369–1379 (2008).
Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).
Eddahri, F. et al. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 113, 2426–2433 (2009).
Linterman, M. A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353–363 (2010).
Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365–378 (2010).
Eto, D. et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS ONE 6, e17739 (2011).
Deenick, E. K. et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33, 241–253 (2010). The study provides strong evidence that development of T FH cells (that is, defined as CXCR5 + PD1 + cells) requires continuous exposure to antigen and does not involve unique inductional signals from the cognate B cells.
Goenka, R. et al. Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J. Immunol. 187, 1091–1095 (2011).
Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 1–15 (2011). This study proposes the first cellular model that can coherently explain how ICOS is required for the GC response by promoting T FH cell development, although experimental evidence taken to support an ICOS→BCL-6→CXCR5 instructional pathway is open to alternative interpretations.
Bauquet, A. T. et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10, 167–175 (2009).
Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).
Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012). This study demonstrates that IL-2 signalling suppresses the development of T FH cells in a manner that does not require T reg cells.
Johnston, R. J., Choi, Y., Diamond, J. A., Yang, J. A. & Crotty, S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243–250 (2012).
Nurieva, R. I. et al. STAT5 negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287, 11234–11239 (2012).
McDonald, P. W. et al. IL-7 signalling represses Bcl-6 and the TFH gene program. Nat. Commun. 7, 10285 (2016).
Liu, X., Nurieva, R. I. & Dong, C. Transcriptional regulation of follicular T-helper (Tfh) cells. Immunol. Rev. 252, 139–145 (2013).
Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat. Immunol. 12, 536–543 (2011).
Bollig, N. et al. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc. Natl Acad. Sci. USA 109, 8664–8669 (2012).
Choi, Y. S., Eto, D., Yang, J. A., Lao, C. & Crotty, S. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190, 3049–3053 (2013).
Ray, J. P. et al. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40, 367–377 (2014).
Ma, C. S. et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119, 3997–4008 (2012).
Schmitt, N. et al. IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121, 3375–3385 (2013).
Xu, L. et al. The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nat. Immunol. 16, 991–999 (2015).
Choi, Y. S. et al. LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol. 16, 980–990 (2015).
Wu, T. et al. TCF1 is required for the T follicular helper cell response to viral infection. Cell Rep. 12, 2099–2110 (2015).
Xiao, N. et al. The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat. Immunol. 15, 657–666 (2014).
Stone, E. L. et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42, 239–251 (2015).
Wang, H. et al. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15, 667–675 (2014).
Liu, X. et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507, 513–518 (2014). This study identifies ASCL2 as a specific transcription factor that directly binds to and upregulates expression of Cxcr5.
Weber, J. P. et al. ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2. J. Exp. Med. 212, 217–233 (2015). An extensive study of the role of ICOS in T FH cell development and maintenance, showing that continuous ICOS signalling in the follicle is important for inactivating FOXO1 and KLF2, which induces T FH cell-incompatible localization properties.
Lee, J. Y. et al. The transcription factor KLF2 restrains CD4 + T follicular helper cell differentiation. Immunity 42, 252–264 (2015).
Hatzi, K. et al. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212, 539–553 (2015).
Vinuesa, C. G. & Cyster, J. G. How T cells earn the follicular rite of passage. Immunity 35, 671–680 (2011).
Arnold, C. N., Campbell, D. J., Lipp, M. & Butcher, E. C. The germinal center response is impaired in the absence of T cell-expressed CXCR5. Eur. J. Immunol. 37, 100–109 (2007).
Liu, X. et al. Genome-wide analysis identifies Bcl6-controlled regulatory networks during T follicular helper cell differentiation. Cell Rep. 14, 1735–1747 (2016).
Kusam, S., Toney, L. M., Sato, H. & Dent, A. L. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170, 2435–2441 (2003).
Mondal, A., Sawant, D. & Dent, A. L. Transcriptional repressor BCL6 controls Th17 responses by controlling gene expression in both T cells and macrophages. J. Immunol. 184, 4123–4132 (2010).
Reinhardt, R. L., Liang, H. E. & Locksley, R. M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385–393 (2009).
Zaretsky, A. G. et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991–999 (2009).
Yusuf, I. et al. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J. Immunol. 185, 190–202 (2010).
Hirota, K. et al. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 14, 372–379 (2013).
Ballesteros-Tato, A. et al. T follicular helper cell plasticity shapes pathogenic T helper 2 cell-mediated immunity to inhaled house dust mite. Immunity 44, 259–273 (2016).
Morita, R. et al. Human blood CXCR5 + CD4 + T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108–121 (2011).
Lee, S. K. et al. Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37, 880–892 (2012).
Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).
Mitsdoerffer, M. et al. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl Acad. Sci. USA 107, 14292–14297 (2010).
Oestreich, K. J. et al. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15, 957–964 (2014).
Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).
Ray, J. P. et al. The Interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690–702 (2015).
Crotty, S., Johnston, R. J. & Schoenberger, S. P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114–120 (2010). An excellent review of the antagonism between BCL-6 and BLIMP1 in the context of memory formation.
Pepper, M., Pagan, A. J., Igyarto, B. Z., Taylor, J. J. & Jenkins, M. K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35, 583–595 (2011). This study shows that, during Listeria monocytogenes infection, cells of central memory features express both CCR7 and CXCR5 and develop in a Bcl-6 and ICOSL-dependent manner, implying there is an intimate relationship between memory T cells and T FH cells.
Qi, H., Liu, D., Ma, W., Wang, Y. & Yan, H. Bcl-6 controlled TFH polarization and memory: the known unknowns. Curr. Opin. Immunol. 28, 34–41 (2014).
Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).
O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).
Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).
Lu, K. T. et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35, 622–632 (2011).
MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
MacLennan, I. C. et al. The changing preference of T and B cells for partners as T-dependent antibody responses develop. Immunol. Rev. 156, 53–66 (1997).
Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).
van Kooten, C. & Banchereau, J. CD40-CD40 ligand. J. Leukoc. Biol. 67, 2–17 (2000).
Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).
McAdam, A. J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001).
Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001).
Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L. & Ahmed, R. SAP is required for generating long-term humoral immunity. Nature 421, 282–287 (2003).
Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).
Cunningham, A. F., Serre, K., Mohr, E., Khan, M. & Toellner, K. M. Loss of CD154 impairs the Th2 extrafollicular plasma cell response but not early T cell proliferation and interleukin-4 induction. Immunology 113, 187–193 (2004).
Lesley, R., Kelly, L. M., Xu, Y. & Cyster, J. G. Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival. Proc. Natl Acad. Sci. USA 103, 10717–10722 (2006).
Smith, K. M. et al. Th1 and Th2 CD4 + T cells provide help for B cell clonal expansion and antibody synthesis in a similar manner in vivo. J. Immunol. 165, 3136–3144 (2000).
Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).
Chan, T. D. et al. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 183, 3139–3149 (2009).
Schwickert, T. A. et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208, 1243–1252 (2011).
Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L. & Germain, R. N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008). This study demonstrates that long-lasting cognate T cell–B cell interactions at the T cell zone–follicle border are promoted by a SAP-dependent signalling process and indicates that GC localization of T FH cells requires such signalling and/or antigen-specific T cell–B cell adhesion.
Chu, C. et al. SAP-regulated T cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions. J. Immunol. 193, 3860–3871 (2014).
Chen, Q. et al. A novel ICOS-independent, but CD28- and SAP-dependent, pathway of T cell-dependent, polysaccharide-specific humoral immunity in response to intact Streptococcus pneumoniae versus pneumococcal conjugate vaccine. J. Immunol. 181, 8258–8266 (2008).
Lee, S. K. et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 208, 1377–1388 (2011).
Allen, C. D., Okada, T., Tang, H. L. & Cyster, J. G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).
Kerfoot, S. M. et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34, 947–960 (2011).
Shulman, Z. et al. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345, 1058–1062 (2014).
Liu, D. et al. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517, 214–218 (2015). This study shows that GC B cells acquire help signals from T FH cells through short, reiterative 'entangled' contacts and that an ICOSL-driven intercellular positive feedback is essential for normal affinity maturation.
Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010). By a fate-mapping strategy based on photoactivatable GFP, this study analyses GC B cell dynamics in detail, identifies light zone and dark zonemarkers and provides the strongest evidence for cyclic re-entry model of affinity maturation that obligately depends on T FH cells.
Tarlinton, D. & Good-Jacobson, K. Diversity among memory B cells: origin, consequences, and utility. Science 341, 1205–1211 (2013).
Casamayor-Palleja, M., Khan, M. & MacLennan, I. C. A subset of CD4 + memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J. Exp. Med. 181, 1293–1301 (1995).
Gitlin, A. D., Shulman, Z. & Nussenzweig, M. C. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014).
MacLennan, I. C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).
Ettinger, R., Kuchen, S. & Lipsky, P. E. The role of IL-21 in regulating B-cell function in health and disease. Immunol. Rev. 223, 60–86 (2008).
Victora, G. D. et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120, 2240–2248 (2012).
Luthje, K. et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 13, 491–498 (2012). A comprehensive study of T FH cells using the first reporter strain for IL-21.
Suan, D. et al. T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. Immunity 42, 704–718 (2015).
Chen, G. et al. Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel. J. Immunol. 185, 2350–2359 (2010).
Toellner, K. M. et al. T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching. J. Exp. Med. 187, 1193–1204 (1998).
Huse, M., Lillemeier, B. F., Kuhns, M. S., Chen, D. S. & Davis, M. M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006).
Kupfer, A., Mosmann, T. R. & Kupfer, H. Polarized expression of cytokines in cell conjugates of helper T cells and splenic B cells. Proc. Natl Acad. Sci. USA 88, 775–779 (1991).
Maldonado, R. A., Irvine, D. J., Schreiber, R. & Glimcher, L. H. A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 431, 527–532 (2004).
Dustin, M. L., Chakraborty, A. K. & Shaw, A. S. Understanding the structure and function of the immunological synapse. Cold Spring Harb Perspect Biol 2, a002311 (2010).
Depoil, D. et al. Immunological synapses are versatile structures enabling selective T cell polarization. Immunity 22, 185–194 (2005).
Qi, H. et al. Follicular T-helper cells: controlled localization and cellular interactions. Immunol. Cell Biol. 92, 28–33 (2014).
Katz, D. H., Hamaoka, T. & Benacerraf, B. Cell interactions between histoincompatible T and B lymphocytes. II. Failure of physiologic cooperative interactions between T and B lymphocytes from allogeneic donor strains in humoral response to hapten-protein conjugates. J. Exp. Med. 137, 1405–1418 (1973).
Katz, D. H., Hamaoka, T., Dorf, M. E. & Benacerraf, B. Cell interactions between histoincompatible T and B lymphocytes. The H-2 gene complex determines successful physiologic lymphocyte interactions. Proc. Natl Acad. Sci. USA 70, 2624–2628 (1973).
Singer, A., Hathcock, K. S. & Hodes, R. J. Cellular and genetic control of antibody responses. V. Helper T-cell recognition of H-2 determinants on accessory cells but not B cells. J. Exp. Med. 149, 1208–1226 (1979).
Singer, A., Hathcock, K. S. & Hodes, R. J. Cellular and genetic control of antibody responses. VIII. MHC restricted recognition of accessory cells, not B cells, by parent-specific subpopulations of normal F1 T helper cells. J. Immunol. 124, 1079–1085 (1980).
Honda, T. et al. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40, 235–247 (2014).
Faroudi, M., Zaru, R., Paulet, P., Muller, S. & Valitutti, S. Cutting edge: T lymphocyte activation by repeated immunological synapse formation and intermittent signaling. J. Immunol. 171, 1128–1132 (2003).
Clark, C. E., Hasan, M. & Bousso, P. A role for the immediate early gene product c-fos in imprinting T cells with short-term memory for signal summation. PLoS ONE 6, e18916 (2011).
Marangoni, F. et al. The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity 38, 237–249 (2013).
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
Xiao, G., Deng, A., Liu, H., Ge, G. & Liu, X. Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. Proc. Natl Acad. Sci. USA 109, 15419–15424 (2012).
Chen, X., Ma, W., Zhang, T., Wu, L. & Qi, H. Phenotypic Tfh development promoted by CXCR5-controlled re-localization and IL-6 from radiation-resistant cells. Protein Cell 6, 825–832 (2015).
Baumjohann, D. et al. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38, 596–605 (2013).
Kageyama, R. et al. The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity 36, 986–1002 (2012).
Pedros, C. et al. A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center T cells via the kinase TBK1. Nat. Immunol, http://dx.doi.org/10.1038/ni.3463 (2016).
Qi, H. From SAP-less T cells to helpless B cells and back: dynamic T-B cell interactions underlie germinal center development and function. Immunol. Rev. 247, 24–35 (2012).
Xu, H. et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 496, 523–527 (2013). This study reveals a costimulation-independent function of ICOS in promoting T cell motility and an essential role for bystander B cells in controlling T FH cell development and localization in an ICOSL-dependent manner.
Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008).
Kerdiles, Y. M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).
Leavenworth, J. W., Verbinnen, B., Yin, J., Huang, H. & Cantor, H. A p85α-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells. Nat. Immunol. 16, 96–106 (2015).
Gigoux, M. et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 106, 20371–20376 (2009).
Kang, S. G. et al. MicroRNAs of the miR-17 ∼ 92 family are critical regulators of TFH differentiation. Nat. Immunol. 14, 849–857 (2013).
Baumjohann, D. et al. The microRNA cluster miR-17 ∼ 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat. Immunol. 14, 840–848 (2013).
Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008).
Vogel, K. U. et al. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38, 655–668 (2013).
Pratama, A. et al. Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity 38, 669–680 (2013).
Pratama, A. et al. MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat. Commun. 6, 6436 (2015).
Tan, A. H., Wong, S. C. & Lam, K. P. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J. Biol. Chem. 281, 28666–28678 (2006).
Qi, H., Kastenmuller, W. & Germain, R. N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue. Ann. Rev. Cell Dev. Biol. 30, 141–167 (2014).
Tubo, N. J. et al. Single naive CD4 + T cells from a diverse repertoire produce different effector cell types during infection. Cell 153, 785–796 (2013).
Fukuda, T. et al. The murine BCL6 gene is induced in activated lymphocytes as an immediate early gene. Oncogene 11, 1657–1663 (1995).
Baumjohann, D., Okada, T. & Ansel, K. M. Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187, 2089–2092 (2011).
Mempel, T. R., Henrickson, S. E. & Von Andrian, U. H. T-Cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).
Miller, M. J., Safrina, O., Parker, I. & Cahalan, M. D. Imaging the single cell dynamics of CD4 + T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).
Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).
Harker, J. A., Lewis, G. M., Mack, L. & Zuniga, E. I. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334, 825–829 (2011).
Leon, B., Bradley, J. E., Lund, F. E., Randall, T. D. & Ballesteros-Tato, A. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat. Commun. 5, 3495 (2014).
Marshall, H. D. et al. The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Elife 4, e04851 (2015).
Hardtke, S., Ohl, L. & Forster, R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 106, 1924–1931 (2005).
Li, J., Lu, E., Yi, T. & Cyster, J. G. EBI2 augments Tfh cell fate by promoting interaction with IL-2- quenching dendritic cells. Nature 533, 110–114 (2016). This study reveals a crucial role for CD4 + CD25 + DCs in facilitating T FH cell development by quenching IL-2 locally at the T cell zone–follicle border.
Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).
Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).
Moriyama, S. et al. Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers. J. Exp. Med. 211, 1297–1305 (2014).
Shulman, Z. et al. T follicular helper cell dynamics in germinal centers. Science 341, 673–677 (2013).
Kitano, M. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34, 961–972 (2011).
He, J. et al. Circulating precursor CCR7 lo PD-1 hi CXCR5 + CD4 + T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39, 770–781 (2013).
Locci, M. et al. Human circulating PD-1 + CXCR3 − CXCR5 + memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 39, 758–769 (2013).
Bentebibel, S. E. et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci. Transl Med. 5, 176ra132 (2013).
Weber, J. P., Fuhrmann, F. & Hutloff, A. T-Follicular helper cells survive as long-term memory cells. Eur. J. Immunol. 42, 1981–1988 (2012).
Fazilleau, N. et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8, 753–761 (2007).
Fazilleau, N., McHeyzer-Williams, L. J., Rosen, H. & McHeyzer-Williams, M. G. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat. Immunol. 10, 375–384 (2009).
Liu, X. et al. Bcl6 expression specifies the T follicular helper cell program in vivo. J. Exp. Med. 209, 1841–1852 (2012).
Choi, Y. S. et al. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J. Immunol. 190, 4014–4026 (2013).
Hale, J. S. et al. Distinct memory CD4 + T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity 38, 805–817 (2013).
Ma, C. S. et al. Early commitment of naive human CD4 + T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol. Cell Biol. 87, 590–600 (2009).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Maciolek, J. A., Pasternak, J. A. & Wilson, H. L. Metabolism of activated T lymphocytes. Curr. Opin. Immunol. 27, 60–74 (2014).
Nakayamada, S. et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919–931 (2011).
Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).
Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K. & O'Shea, J. J. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30, 707–731 (2012).
How AIDS Works
Like all viruses, HIV treads the fine line that separates living things from nonliving things. Viruses lack the chemical machinery that human cells use to support life. So, HIV requires a host cell to stay alive and replicate. To reproduce, the virus creates new virus particles inside a host cell, and those particles carry the virus to new cells. Fortunately the virus particles are fragile.
Viruses, including HIV, don't have cell walls or a nucleus. Basically, viruses are made up of genetic instructions wrapped inside a protective shell. An HIV particle, called a virion, is spherical and has a diameter of about one 10,000th of a millimeter.
HIV infects one particular type of immune system cell. This cell is called the CD4+T cell, a type of white blood cell also known as a T-helper cell. In fact, the virus only targets a subset of the T-helper cells: those that have already been exposed to infection. This is because, unlike "naive" cells, the experienced "memory" cells are in constant motion, and HIV uses that motion in a complex way to get inside them. Once infected, the T-helper cell turns into an HIV-replicating cell. T-helper cells play a vital role in the body's immune response. There are typically 1 million T-cells per 1 milliliter of blood. HIV will slowly reduce the number of T-cells until the person develops AIDS.
HIV is a retrovirus, which means it has genes composed of ribonucleic acid (RNA) molecules. Like all viruses, HIV replicates inside host cells. It's considered a retrovirus because it uses an enzyme, reverse transcriptase, to convert RNA into DNA [source: Lu et al.].
To understand how HIV infects the body, let's look at the virus's basic structure:
Th17 cell activation and differentiation
Like other subsets of T helper cells, Th17 cells differentiate from naive CD4 + cells in the periphery in response to T cell receptor (TCR) antigen stimulation and activating cytokines secreted by antigen-presenting cells . While differentiation was originally believed to be induced by IL-23, it was later demonstrated that Th17 development occurred independently of this cytokine. However, IL-23 is still thought to be important for Th17 maintenance and proliferation, and its receptor (IL-23R) is upregulated in activated Th17 cells . The critical cytokine mediators of Th17 differentiation have instead been identified to be TGFβ in combination with IL-6 or IL-21 [6,7]. IL-6 and IL-21 drive expression of Th17 transcriptional regulators via STAT3 signaling, committing CD4 + T cells to the Th17 lineage. Defects in this signaling pathway have been associated with decreased expression of IL-23R, key Th17-associated transcription factors, and effector cytokines such as IL-17A and IL-17F .
A candidate master regulator of Th17 differentiation was first identified as RORγt, a member of the retinoic acid–related orphan nuclear hormone receptor family . This transcription factor was found to induce expression of IL-17A and IL-17F, and its deficiency was associated with reduced, but not completely absent, Th17 development and function [6,7]. Later studies identified RORα, a related transcription factor, could also drive Th17 differentiation and cytokine expression in response to STAT3 in a similar manner as RORγt . RORα and RORγt act synergistically to promote Th17 commitment, and combined deficiencies in both factors results in complete inhibition of Th17 development .
Other transcription factors that play a role in Th17 development are IRF4, BATF, and AHR. IRF4 is thought to be upstream of RORγt, as the ability of naive CD4 + T cells to upregulate RORγt expression is reduced in its absence, but its exact role in Th17 biology is not fully understood . AHR is a nuclear factor shared with T regulatory cells but expressed at higher levels in Th17 cells, and while its deficiency does not impact Th17 differentiation, the production of effector cytokines, particularly IL-22, is significantly diminished . Lastly, BATF has been demonstrated to be necessary for generation of Th17 cells and expression of their associated cytokines, despite the observation that BATF is not unique to the Th17 lineage and that BATF-deficient cells are still capable of inducing RORα and RORγt .
The Th17 lineage exhibits a high degree of plasticity and has been observed to trans-differentiate into other CD4 + T helper subtypes in response to changing environmental cues. T regulatory cells are another T helper subset that depends on TGFβ for its differentiation increasing concentrations of this cytokine tend to skew naive cells towards Foxp3 expression, which is strongly inhibitory to Th17 development and instead drives commitment towards a regulatory phenotype . Despite this, high levels of IL-6 and resultant STAT3 signaling can downregulate Foxp3 expression in favor of Th17-related genes in TGFβ-induced T regulatory cells, particularly in the presence of IL-1 . While trans-differentiation of Th17 cells has been mainly observed with the Th1 and T regulatory subsets, evidence also exists of shared functions with Th2, T follicular helper, and TR1 cells . The observation that multiple transcriptional master regulators of different CD4 + T helper cell subsets can be co-expressed further confirms the potential for functional flexibility between these lineages .
Figure 1. Overview of Th17 differentiation. Naive CD4 + T cells begin their polarization towards the Th17 lineage following STAT3 signaling and RORγt upregulation induced by IL-6 or IL-1 in the presence of TGFβ. IL-21 production maintains Th17 commitment in an autocrine manner, and IL-23 from antigen presenting cells promotes maturation, survival, and effector functions.
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T follicular helper (TFH) cells play a crucial part in the development of humoral immunity by controlling the formation of, and the cellular reactions that occur in, germinal centres. Within these organized lymphoid tissue microstructures, B cells proliferate and somatically mutate to produce long-lived, high-affinity plasma cells and memory B cells. TFH cells exhibit unique molecular, cellular and tissue-dynamic features that are integral to their development and function but that are not necessarily compatible with the classical paradigm of effector CD4 + T cell differentiation. Here, I discuss recent advances in TFH cell biology and their implications for our understanding of T cell differentiation and memory in humoral immunity from spatiotemporal and functional perspectives.
Dr. MATTHEW OLSON
The immune system is comprised of a variety of cell types that work in a highly organized fashion to protect the body from infection and minimize tumor formation. This organizational process is largely carried out by the adaptive immune system with CD4 + T helper (Th) cells acting to trigger inflammation during infection and also suppress unwanted immune responses to non-harmful stimuli (i.e. allergens, food or normal body microflora). The dual nature (i.e. activator and suppressor) of Th cells is possible due to their unique ability to sense the environment and change their function based on these environmental cues.
Autoimmune disease occurs when the balance between the inflammatory and regulatory functions of Th cells is disrupted, resulting in excess inflammation that alters physiological processes. Inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) are two forms of intestinal autoimmune disease and are characterized by the accumulation of highly reactive inflammatory T cells in the intestines. However, the exact mechanisms by which inflammatory Th cells arise during inflammation and cause disease are unclear.
In the Olson lab, our goal is to better understand how CD4 + T helper cells drive intestinal inflammation by addressing these key questions:
1) What signals drive the generation of pathogenic/inflammatory Th cells in the intestines?
2) How do pathogenic/inflammatory T helper cells contribute to disease?
3) Can we therapeutically target factors that drive the generation of pathogenic T helper cells or their functional byproducts to eliminate or reduce disease?
My laboratory uses a combination of cell and molecular biology approaches to examine signaling pathways associated with T helper cell differentiation. We also utilize pre-clinical models of disease, and high throughput culturing and RNA/protein profiling techniques to identify disease mechanisms and novel mediators of inflammation.