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Review: Naive CD4+ T-cells in Autoimmunity & Inflammation

Autoimmunity is attributed to a dysregulation of the adaptive immune response that results in targeting of the body’s own healthy tissues by immune cells. The exact origins of autoimmune responses remain elusive, but a combination of genetic1 and environmental factors2 appear to contribute to the pathogenesis of various autoimmune diseases (ADs). Further adding to this complexity is the various cell types and signaling molecules comprising the biological mechanisms underlying ADs. One cell type, naïve CD4+ T cells, is of particular importance given their ability to modulate pro-inflammatory and anti-inflammatory signals via their differentiation into various T helper (Th) cell lineages. Since inflammation is a hallmark sign of autoimmunity, the balance between Th cell lineages has huge implications for the progression of ADs. This post will provide a brief overview of the differentiation of various Th cell subtypes and the implication of those subtypes in inflammation/autoimmunity. Subsequent posts will explore specific cytokines secreted by Th cell lineages and the role they play in mediating inflammatory responses and autoimmune diseases, namely rheumatoid arthritis.

The adaptive immune response begins when antigen-presenting cells (APCs), such as macrophages and dendritic cells, engulf a foreign substance and process it to produce small peptides (i.e. antigens). These antigens are then “presented” to naïve CD4+ T cells via major histocompatibility complex (MHC) molecules on the surface of APCs. Naïve CD4+ T cells that express T-cell receptors complimentary to the presented antigen will interact with the APC and begin to undergo differentiation to a subtype of T helper cells. There are several factors that contribute to determining which Th cell type is produced3, but the cytokine profile of the CD4+ T cell microenvironment appears to be key4. The first T helper cell lineages identified, type 1 helper T cells (Th1 cells) and type 2 helper T cells (Th2), were discovered in 1986 after experiments in murine models5.

Th1 cells are associated with cell-mediated immunity and are responsible for protection against intracellular infections by bacteria, viruses, and other pathogens. Differentiation of Th1 cells appears to be mediated through naïve CD4+ T cell stimulation by interleukin-12 (IL-12) produced by macrophages6 and dendritic cells7 during antigen presentation. T-box transcription factor (T-bet), STAT1, and STAT4 have been shown to be important transcription factors for promoting Th1 cell differentiation while suppressing differentiation (T-bet) of other T helper cell lineages8,9.  T helper cell lineages are classically defined by secretion of a signature (set of) cytokine(s). For Th1 cells, the identifying cytokines are IFN-gamma and tumor necrosis factor-beta (TNF-beta or lymphotoxin). Other cytokines produced include IL-2 and TNF-alpha. Generally, the cytokines secreted by Th1 cells are considered pro-inflammatory and have been implicated in the pathogenesis of rheumatoid arthritis and organ-specific inflammatory/autoimmune disorders10.  While in depth discussion of the biological mechanisms modulated by these cytokines is outside the scope of this brief review, it is important to note that several cytokines (notably IFN-gamma and IL-12) released by Th1 cells promote Th1 cell differentiation while suppressing Th2 cell proliferation11

Th2 cells promote humoral (antibody-mediated) immune responses against extracellular infections by bacteria, allergens, toxins, helminths and other parasites. Th2 cells are defined by their production of IL-4, IL-5, IL-10 and IL-13 that inhibit macrophage function, promote antibody production (namely IgE) and recruit eosinophils and basophils to sites of infection. Together these cytokines promote allergic immune responses and, therefore, Th2 cells have been implicated in allergic inflammatory disorders12. IL-4 has been shown to be crucial for Th2 cell proliferation in vitro, but its requirement in vivo has been debated since mice deficient in IL-4 and IL-4 receptor genes can still produce Th2 cells13. However, another study shows that transcription factors STAT6 (induced by IL-4) and GATA-binding protein (GATA3) to be crucial in vivo for Th2 cell differentiation14. Additional studies have shown the requirement of STAT3 for optimal interaction of STAT6 with Th2 cell associated gene loci15. As with Th1 cells, Th2 cytokines (specifically IL-4) provide a feedback loop that simultaneously promotes Th2 cell differentiation and suppresses Th1 cell differentiation11.

The Th1/Th2 cell paradigm laid the foundation for a better understanding of T cell biology and adaptive immune responses; however, this paradigm is not comprehensive. Two other distinct T cell lineages, Th17 and inducible regulatory T (iTreg) cells, have been shown to play a vital (and antagonistic) role in inflammatory and autoimmune pathways. Th17 cells and their signature cytokine, IL-17A, promote inflammatory responses and have been implicated in the pathogenesis of rheumatoid arthritis16, inflammatory bowel disease17, and other autoimmune diseases18. Other pro-inflammatory cytokines secreted by Th17 cells include IL-17F, IL-21, and IL-22. iTreg cells, on the other hand, are immunosuppressant and down-regulate the effector functions of Th1, Th2, and Th17 cells. Through secretion of IL-10, TGF-beta, and IL-35, iTreg cells are vital for limiting the tissue damaging effects of cell-mediated and antibody-mediated immune responses. The oppositional roles filled by Th17 and iTreg cells in adaptive immune responses is highlighted by their overlapping differentiation pathways. 

Differentiation of both Th17 and iTreg cells is dependent on the binding of transforming growth factor-beta (TGF-beta) in a concentration dependent manner. At high concentrations, binding of TGF-beta suppresses IL-23 receptor expression and activates the Smad2 pathway that ultimately leads to expression of the transcription factor Foxp3. Foxp3 exerts suppressive effects on the transcription of nuclear factor retinoid-related orphan receptor gamma-T (RORgamma-T), a transcription factor crucial for expression of the Th17 cell phenotype, ultimately leading to iTreg differentiation.  However, the binding of IL-6 or IL-21 (both pro-inflammatory cytokines) in combination with binding of TGF-beta (present in low concentrations) promotes Th17 differentiation. IL-6 and IL-21 work synergistically with TGF-beta to upregulate IL-23 receptor transcription and to activate the STAT3 pathway that disrupts the Foxp3 suppression of RORgamma-T, therefore promoting the Th17 cell phenotype19,20.

While this review is far from exhaustive, it provides a good starting point for further discussion of the important role Th cell lineages and their effector cytokines play in autoimmune pathologies. Future posts will explore this relationship further and elucidate the molecular mechanisms through which Th cell lineages exert their effects and contribute to inflammation and autoimmunity.

 

Keywords: Cytokine, Naive CD4+ T-cell, T helper cell, Autoimmunity, Inflammation, Rheumatoid Arthritis

 

Citations

1.    Shoenfeld, Y., Zandman-Goddard, G., Stojanovich, L., Cutolo, M., Amital, H., et al. The mosaic of autoimmunity: hormonal and environmental factors involved in autoimmune diseases-2008. Isr Med Assoc J. January 2008; 10(1), 8-12.
2.    Shoenfeld, Y., Gilburd, B., Abu-Shakra, M., Amital, H., Barzilai, O. The mosaic of autoimmunity: genetic factors involved in autoimmune diseases-2008. Isr Med Assoc J. January 2008; 10(1), 3-7
3.    Constant, S.L., Bottomly, K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. April 1997; 15(1-879), 297-322. 
doi: 10.1146/annurev.immunol.15.1.297
4.    O’Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity. March 1998; 8(3), 275-283.
5.    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 1986;136:2348–2357.
6.    Hsieh, CS., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O’Garra, A., Murphy, K.M. Development of CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. April 1993; 260(5107), 547-549. PMID: 8097338
7.    Macatonia, S.E., Hosken, N.A., Litton, M., Vieira, P., Hsieh, CS., Culpepper, J.A., Trinchieri, G., Murphy, K.M., O’Garra, A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naïve CD4+ T cells. J Immunol. May 1995; 154(10), 5071-5079.
8.    Lazarevic, V., Glimcher, L.H., Lord, G.M. T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol. October 2013; 13, 777-789. doi: 13.1038/nri3536
9.    Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T.L., Murphy, K.M. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol. May 2002; 3, 549-557. doi: 10.1038/ni794
10.    Damsker, J.M., Hansen, A.M., Caspi, R.R. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci. January 2010; 1183, 211-221. doi: 10.1111/j.1749-6632.2009.05133.x
11.    Glimcher, L.H., Murphy, K.M. Lineage commitment in the immune system: the T help lymphocyte grows up. Genes & Dev. 200; 14, 1693-1711
12.    Maggi, E. The Th1/Th2 paradigm in allergy. Immunotechnology. January 1998; 3(4), 233-244.
13.    Panhuys, N.v., Tang, S-C., Prout, M., Camberis, M., Scarlett, D., Roberts, J., Hu-Li, J., Paul, W.E., Gros, G.L. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. PNAS. July 2008; 105(34), 12423-12428. doi: 10.1073/pnas.0806372105
14.    Horiuchi, S., Onodera, A., Hosokawa, H., Watanabe, Y. Tanaka, T., Sugano, S., Suzuki, Y., Nakayama, T. Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. J Immunol. June 2011; 186(11), 6378-6389. doi: 10.4049/jimmunol.1100179
15.    Stritesky, G.L., Muthukrishnan, R., Sehra, S. Goswamu, R., Pham, D., Travers, J., Nguyen, E.T., Levy, D.E., Kaplan, M.H. The transcription factor STAT3 is required for T helper 2 cell development. Immunity. January 2011; 34(1), 39-49. doi: 10.1016/j.immuni.2010.12.013
16.    Kotake, S., Udagawa, N., Takahasi, N. Matsuzaki, K., et al. IL-17 in synovial fluids from patients with trheumatoid arthritis is a potent stimulator of osetoclastogenesis. J Clin Invest. May 1999; 103(9), 1345-1352. doi: 10.1172/JCI5703
17.    Zenewicz, L.A., Antov, A., Flavell, R.A. CD4 T-cell differentiation and inflammatory bowel disease. Trends in Molecular Medicine. May 2009; 15(5), 199-207. doi: 10.1016/j.molmed.2009.03.002
18.    Tabarkiewicz, J. Pogoda, K., Karczmarczyk, A., Pozarowski, P., Giannopoulos, K. Th role of Il-17 and Th17 lymphocytes in autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2015; 63, 435-449. doi: 10.1007/s00005-15-0344-z
19.    Zhou, L., Lopes, J.E., Chong, M.M.W., Ivanov, I.I., Min, R., et al. TGF-β-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORγt function. Nature. May 2008; 453, (236-240).                doi: 10.1038/nature06878
20.    Hori, S., Nomura, T., Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science. February 2003; 299(5609), 1057-1061. doi: 10.1123/science.1079490