Immune response - Th1 and Th2 cell differentiation

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Th1 and Th2 cell differentiation

Naive CD4+ T cells are activated by recognition of a peptide antigen-class II major histocompatibility complex (MHC class II) presented on antigen-presenting cells (APCs) through interaction with the T-cell receptor (TCR alpha/beta). After activation, CD4+ T cells begin to divide and/or give rise to a clone of effector cells, each specific for the same antigen-class II MHC complex. These effector CD4+ T cells can be divided into three main types, T helper type-1 (Th1), Th type-2 (Th2), and Th type-17 (Th17), with distinct cytokine-secretion phenotypes. Th1 cells secrete mainly Interferon gamma (IFN-gamma), which allows these cells to be particularly effective in protecting against viruses and bacteria. IFN-gamma activates macrophages, enhancing their ability to phagocytoseand destroy microbes. Th2 cells produce mainly Interleukin 4 (IL-4), IL-5, and IL-13, which up-regulate antibody production and target parasitic organisms. IL-4 and IL-13 induce B cell switching to IgE production, whereas IL-5 is the principal eosinophil-activating cytokine, mediating allergic reaction. In broad terms, Th1 cells mediate a cellular immune response and Th2 cells potentiate a humoral immune response [1].

Until recently Th1 and Th2 cell subsets were considered to be the only types of CD4+ effector responses. Studies over the last few years have discovered a new subset known as Th17 cells. These cells preferentially produce IL-17, IL-17F, and IL-22 as their signature cytokines and play an integral role in tissue inflammation and activation of neutrophils [2].

Direct contact of APCs with T cells is the first step in Th cell differentiation. Pathogen-associated molecular patterns are recognized by APCs (macrophages and dendritic cells), which present antigenic components (Antigen) bound to MHC class II. APCs mould the T-cell response in accordance with the nature of the invading pathogen. Pathogens express pathogen-associated molecular patterns that activate APCs directly through ligation of pattern recognition receptors. The most common receptors involved in pattern recognition are the Toll-like receptors (TLRs), which discriminate between different types of pathogens [1]. TLR signaling leads to the activation of Nuclear factor of kappa-B (NF-kB), the main transcription factor involved in cytokine production [3].

Stimulation of TCR alpha/beta/ CD3 complex on T cells by MHC class II on APCs initiates a T cell signaling cascade leading to the activation of Nuclear factors of activated T-cells, e.g. NF-AT1(NFATC2) and NF-AT2(NFATC1), NF-kB, and transcription factors of the Activator protein 1 (AP-1) family [4], [5], [6], [7]. These transcription factors activate Interleukin 2 (IL-2) production and increase T cell proliferation [5].

In addition to TCR alpha/beta, a whole set of cell-surface receptors are also engaged by their ligands on APCs, which regulate the Th differentiation program. CD4 acts as a cellular adhesion molecule that binds MHC class II and stabilizes the interaction of T cells and APCs [8], [9]. CD28 is the most notable costimulatory receptor on T cells. It binds CD80 and CD86 on activated APCs [10]. The TCR alpha/beta / CD3 complex provides a first signal for T cell activation, and CD28 provides the second. Both signals are required for Interleukin 2 (IL-2) production and T cell proliferation. CD40 ligand (CD40L), which is expressed by activated T cells, binds to CD40 on APCs. This interaction is crucial for T-cell-mediated immune response [11].

IL-12 is considered to be the main cytokine driving Th1 cell differentiation. IL-12 is produced mainly by macrophages and dendritic cells, but also by monocytes, neutrophils, and B cells in response to different pathogens. IL-12 induces IFN-gamma production in natural killer (NK) cells, APCs and T cells, an effect that is synergistically enhanced by the unrelated cytokine IL-18. IFN-gamma is also produced by APCs as a result of the TLR signaling pathway in response to bacteria and viruses [12], [13].

IL-12 binds to the IL-12 receptor, which is composed of two subunits, IL-12R beta 1 and IL-12R beta 2 (IL-12RB2). IL-12 receptor activates the Janus kinases (Tyk2 and JAK2) and the Transcription factor signal transducer and activator of transcription 4 (STAT4), which up-regulates IFN-gamma and IL-12RB2 gene expression [14]. IFN-gamma attachment to IFN-gamma receptor leads to the JAK1- and JAK2-mediated activation of the transcription factor STAT1 that then induces expression of the another transcription factor, T-box 21 (T-bet). T-bet increases expression of IFN-gamma and IL-12RB2, which reinforces IL-12 and IFN-gamma signaling pathways [12], [13], [15].

IL-4 is the main cytokine driving Th2 cell differentiation. IL-4 can be produced by many cell types, such as mast cells, basophils, eosinophils, NK cells, activated CD4+ T cells and differentiated Th2 cells [13]. IL-4 binds to IL-4 receptor, type I (IL-4R type I), which induces JAK1 / STAT6 signaling in T cells. STAT6, in turn, activates the expression of transcription factors GATA binding protein 3 (GATA-3) and v-Maf musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf), leading to IL-4, IL-5, and IL-13 production [1], [12], [13].

Differentiated Th cells suppress the development of their opposing cell subset. For instance, they inhibit expression of the opposing cytokine genes [1]. In Th1 cells, the Runt-related transcription factor 3 (RUNX3) is induced in a T-bet-dependent manner, and both transcription factors T-bet and RUNX3 regulate maximal production of IFN-gamma and silencing of the gene encoding IL-4, the main cytokine required for Th2 cell differentiation [16]. GATA-3, the key transcription factor of Th2 cell differentiation, significantly inhibits expression of IFN-gamma, the main cytokine produced by Th1 cells [12], [17].

References:

  1. Kaiko GE, Horvat JC, Beagley KW, Hansbro PM
    Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology 2008 Mar;123(3):326-38
  2. Ghilardi N, Ouyang W
    Targeting the development and effector functions of TH17 cells. Seminars in immunology 2007 Dec;19(6):383-93
  3. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  4. Rusnak F, Mertz P
    Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
  5. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  6. Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML
    The immunological synapse. Annual review of immunology 2001;19:375-96
  7. Nel AE
    T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. The Journal of allergy and clinical immunology 2002 May;109(5):758-70
  8. Leitenberg D, Boutin Y, Constant S, Bottomly K
    CD4 regulation of TCR signaling and T cell differentiation following stimulation with peptides of different affinities for the TCR. Journal of immunology (Baltimore, Md. : 1950) 1998 Aug 1;161(3):1194-203
  9. Krummel MF, Sjaastad MD, Wülfing C, Davis MM
    Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 2000 Aug 25;289(5483):1349-52
  10. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M
    CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. Journal of immunology (Baltimore, Md. : 1950) 1995 Jan 1;154(1):97-105
  11. Dong C, Flavell RA
    Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis research 2000;2(3):179-188
  12. Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O'Shea JJ, Frucht DM
    Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. Journal of clinical immunology 2003 May;23(3):147-61
  13. Rautajoki KJ, Kylaniemi MK, Raghav SK, Rao K, Lahesmaa R
    An insight into molecular mechanisms of human T helper cell differentiation. Annals of medicine 2008;40(5):322-35
  14. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ
    Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological reviews 2004 Dec;202:139-56
  15. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM
    T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nature immunology 2002 Jun;3(6):549-57
  16. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM
    Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nature immunology 2007 Feb;8(2):145-53
  17. Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, Arai N, O'Garra A
    GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clinical immunology (Orlando, Fla.) 1999 May;91(2):134-44

  1. Kaiko GE, Horvat JC, Beagley KW, Hansbro PM
    Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology 2008 Mar;123(3):326-38
  2. Ghilardi N, Ouyang W
    Targeting the development and effector functions of TH17 cells. Seminars in immunology 2007 Dec;19(6):383-93
  3. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  4. Rusnak F, Mertz P
    Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
  5. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  6. Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML
    The immunological synapse. Annual review of immunology 2001;19:375-96
  7. Nel AE
    T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. The Journal of allergy and clinical immunology 2002 May;109(5):758-70
  8. Leitenberg D, Boutin Y, Constant S, Bottomly K
    CD4 regulation of TCR signaling and T cell differentiation following stimulation with peptides of different affinities for the TCR. Journal of immunology (Baltimore, Md. : 1950) 1998 Aug 1;161(3):1194-203
  9. Krummel MF, Sjaastad MD, Wülfing C, Davis MM
    Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 2000 Aug 25;289(5483):1349-52
  10. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M
    CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. Journal of immunology (Baltimore, Md. : 1950) 1995 Jan 1;154(1):97-105
  11. Dong C, Flavell RA
    Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis research 2000;2(3):179-188
  12. Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O'Shea JJ, Frucht DM
    Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. Journal of clinical immunology 2003 May;23(3):147-61
  13. Rautajoki KJ, Kylaniemi MK, Raghav SK, Rao K, Lahesmaa R
    An insight into molecular mechanisms of human T helper cell differentiation. Annals of medicine 2008;40(5):322-35
  14. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ
    Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological reviews 2004 Dec;202:139-56
  15. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM
    T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nature immunology 2002 Jun;3(6):549-57
  16. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM
    Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nature immunology 2007 Feb;8(2):145-53
  17. Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, Arai N, O'Garra A
    GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clinical immunology (Orlando, Fla.) 1999 May;91(2):134-44

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