Lecture 12 - CD4 T cell subsets (Th17 & Treg)

• Pathogens targeted by Th17 cells

  • Extracellular bacteria
  • Fungi
• Th17 cells


  • Specialized in coordinating effector immune responses against pathogens that cannot be cleared by Th1 or Th2 cells
• How Th17 cells combat extracellular bacteria

  1. Th17 cells produce IL-17

  2. IL-17 induces non-immune cells to produce CXCL8

  3. CXCL8 functions as a neutrophil chemoattractant

  4. Recruiting neutrophils to the site of infection to help eliminate the extracellular bacteria
• How Th17 cells combat fungal infections

  1. Dendritic cells produce active TGF beta, IL-6, and IL-23 in response to fungi

  2. TGF beta and IL-6 serve as the signal 3 for Th17 differentiation

  3. IL-23 further promotes the expansion and survival of Th17 cells

  4. Th17 cells recruited to sites of inflammation also recruit neutrophils to aid in the elimination of fungal pathogens
• Signal 3 for Th17 differentiation

  Production of active TGF beta and IL-6 in response to fungi or extracellular bacteria
• Role of dendritic cells

  • Recognize pathogen-associated molecular patterns (PAMPS) through pattern recognition receptors (PRRs)
  • Present antigens to naive CD4 T cells
  • Binding of PAMPS to DC PRRs triggers the production of active TGF beta and IL-6
• Downstream signalling pathways in Th17 cells

  1. IL-6 and TGF beta induce initial differentiation of Th17 cells by activating the STAT3 pathway

  2. ROR-gamma-t is the lineage-specific transcription factor for Th17 cells, induced by TGF beta and IL-6

  3. IL-23 promotes the expansion and survival of Th17 cells

  4. Th17 cells produce IL-17, which induces non-immune cells to produce CXCL8 as a neutrophil chemoattractant
• Oppmann et al Immunity (2000) identified IL-23 as a heterodimer of IL-12p40 and IL-23p19 subunits
• Knockout studies involving IL-12 or IL-23 alone revealed that IL-23, not IL-12, is responsible for causing brain inflammation associated with Th17 response
• Langrish et al JEM 2005 demonstrated that impaired Th17 response led to no disease, while impaired Th1 response led to enhanced disease, further confirming the role of IL-23 in Th17 identification
• Wildtype and knockout mouse models were used to study the effects of IL-12 and IL-23 on Th17 response and autoimmune inflammation, providing crucial evidence for the identification of Th17 cells
• Regulatory T cells (Tregs)


  • Essential for maintaining peripheral tolerance and preventing autoimmune diseases
  • Play a crucial role in turning off immune responses and preventing the activation of self-reactive T cells
• Types of Tregs


  • Natural Tregs (nTregs)
  • Induced Tregs (iTregs)
• Natural Tregs (nTregs)


  • Differentiate in the thymus in response to stronger than normal T cell receptor (TCR) stimulation, but not strong enough to delete the Treg
  • Involves the expression of Foxp3 transcription factor
• Induced Tregs (iTregs)


  Differentiate in the periphery in response to the presence of TGF beta in the absence of inflammatory signals
• Relationship between Tregs and Th17 cells

  • Tregs and Th17 cells have a reciprocal relationship, as they both arise from the same precursor cells and share some common signalling pathways
  • TGF beta and IL-6 induce the differentiation of both Tregs and Th17 cells, but the presence of IL-23 promotes Th17 expansion and survival
• How Tregs suppress immune responses

  1. Expressing high levels of CTLA-4, which binds to and sequesters CD80 and CD86 on APCs, preventing their interaction with naive T cells

  2. Expressing high levels of the IL-2 receptor, which allows Tregs to outcompete activated T cells for IL-2, thereby stopping their proliferation

  3. Secretion of immunosuppressive cytokines, such as IL-10 and TGF beta, which inhibit the production of pro-inflammatory cytokines by dendritic cells, reduce antigen presentation, and directly inhibit T cell proliferation