T cell mediated responses I

• What is the main function of having distinct CD4+ T cell subsets?

  CD4+ T cell subsets respond to different types of pathogen and secrete specific cytokines that help tailor the effector responses. Different CD4+ T cell subsets include Th1, Th2, Th17, Tfh and Th9 cells, which all promote immune response and regulatory T cells, which suppress immune responses.
• Describe the function of IL-2 in CD4+ T cell differentiation

  IL-2 is a growth factor that drives T cell proliferation in both an Paracrine and autocrine manner (activated CD4+ T cells can produce IL-2 to act on itself).
• What is the function of signal 3 in T cell activation?

  Signal 3 triggers intracellular signals that promote differentiation of CD4+ T cell. This occurs via epigenetic changes that drive expression of distinct transcriptional machinery that drive differentiation and proliferation of a certain CD4+ T cell subset. These differentiation changes are heritable during clonal expansion so that the subset is stabilised.
• Describe the difference in function of Th1 and Th2 subsets

  Functionally specialised to deal with the different types of infection:

  • Th1: essential in response to intracellular pathogens, .e.g, viruses and some bacteria
  • Th2: essential in responses to extracellular pathogens, e.g., parasitic worms
• Describe Th1 cell differentiation

  • IL-2 induces proliferation via STAT5 signalling
  • Stabilising factors, which promote Th1 specific T-bet expression
  • IFN-gamma and IL-27 via STAT1 signalling
  • IL-12 via STAT4 signalling
  • Activated Th1 cell secretes: IFN-gamma, TNF-alpha, TNF-beta and IL-2, which feeds back into Th1 differentiation
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  Describe the function of Th1 cells

  These are key activators of cell-mediated immunity, in order to kill virally infection cells:

  • IFN-gamma: activates macrophages
  • IL-2 and IFN-gamma: activate CD8+ cytotoxic T cells
• Describe Th2 cell differentiation

  • IL-2 induces proliferation via STAT5 signalling
  • IL-4 promotes and stabilises expression of Th2 specific transcription factor GATA3 via STAT6 signalling
  • Activated Th2 cells secrete: IL-3, IL-5, IL-9, IL-13 and IL-4, which feeds back and promoters differentiation of more Th2 cells
• Describe Th2 cell function

  Th2 cells generally deal with large extracellular worms by secreting specific cytokines:

  • IL-13: promotes epithelial cell repair, mucus production, and smooth muscle contraction
  • IL-4 and IL-13: promoters M2 like macrophage differentiation to promote tissue repair
  • IL-5: promotes eosinophil recruitment and activation
  • IL-3 and IL-9: promotes mast cell recruitment
• Describe the positive feedback loop that drives Th1 cell differentiation

  • IFN-gamma is secreted by accessory cells, e.g., NK cells, and helps drive Th1 differentiation via upregulation of T-bet
  • IFN-gamma is produced by Th1 cells and feeds back to further drive T-bet and IFN-gamma expression
  • T-bet drives expression of IL-12 receptor, with IL-12 further promoting Th1 differentiation
  • This stabilises the Th1 phenotype and polarises the immune response.
• Describe the positive feedback loop that reinforces Th2 cell differentiation

  • Accessory cells, e.g., basophils, secrete IL-4, which drives Th2 differentiation via the upregulation of GATA-3
  • IL-4 is produced by Th2 cells and feeds back to further drive GATA-3 and IL-4 expression.
• Describe cross-inhibition of Th1 and Th2 cell differentiation

  • In Th1 cells, T-bet inhibits expression of GATA-3
  • In Th2 cells, GATA-3 inhibits expression of T-bet

  This enables an appropriate polarised CD4+ T cell response
• Describe the action of Th17 cells

  Th17 cells deal with fungal and extracellular bacterial pathogens. They are also one of the key cells in several autoimmune diseases, such as IBD, Rheumatoid arthritis and MS.
• Describe Th17 cell differentiation

  • TGF-beta, via Smad signalling, and IL-6, via STAT3 signalling, promote the expression of Th17 specific transcription factors ROR-alpha and ROR-gamma-t
  • IL-23, IL-21 and IL-1-beta also promote Th17 differentiation and expansion
  • IL-2 inhibit Th17 differentiation
  • Activated Th17 cells secrete: IL-17A, IL-17F and IL-21, which feeds back to promote Th17 differentiation
• Describe Th17 cell function

  Th17 cells secrete Il-17, which modulates immune response by inducing expression of different immunomodulatory molecules:

  • Recruitment of neutrophils: IL-17 drives CXCL2 production, which is the neutrophil recruitment factor
  • Anti-microbial protein induction: IL-17 induced genes include RegIII-gamma and RegII-beta, and S100A8, which sequesters calcium in the environment
• What is the main function of Tfh cells?

  These cells promote B cell responses
• Describe Tfh cell differentiation

  • IL-6 and IL-21 , via STAT3 signalling, promote expression of Bcl-6, which inhibits BLIMP-1 expression. BLIMP-1 is a negative regulator of specific transcription factors
  • This allows activated Tfh cells to secrete CXCR5, which is a chemokine receptor that mediates Tfh cell migration to B cell follicle
  • Tfh cells also secrete IL-21, which feeds back to promote Tfh cell differentiation
• Describe the Tfh1 cells

  • Expresses Bcl-6 and T-bet
  • Secretes IL-21 and IFN-gamma
  • Promotes production of IgG2A and IgG2c
  • important in clearing intracellular viral infections
• Describe Tfh2 cells

  • Express Bcl-6 and GATA-3
  • Secrete IL-21, IL-4 and IL-13
  • Promote production of IgE
  • Mast cell activation and promotes clearance of large pathogens in the GI tract
• Describe Tfh17 cells

  • Express Bcl-6 and ROR-gamma-t
  • Secrete IL-21 and IL-17
  • Promote production of IgG2a and IgG3
• Describe Tfr cells

  • Express Bcl-6 and FoxP3
  • Secrete CTLA-4
  • Suppress B cell responses