T cell activation and differentiation 2

• Describe and compare the two different CD4+ T cell subsets

  Th1 cells: essential in responses to intracellular pathogens (e.g., viruses)

  • Produce IL-2, IFN-gamma and lymphotoxin (LT)
  • Activate macrophages and stimulate CD8+ T cells

  Th2 cells: essential in responses to extracellular pathogens (e.g., parasitic worms)

  • Produce IL-4, IL-5, IL-9 and IL-13
  • Attract and activate eosinophils and basophils and help promote tissue repair
• Describe the different signals require to activate CD4+ T cells

  Signal 1: recognition by CD4+ T cell receptor of antigen presented by MHCII

  Signal 2: co-stimulatory molecule interaction, e.g., CD28 with CD80/86 (strengthened by adhesion receptors, e.g., LFA1 with ICAM1)

  Signal 3: cytokine signals required for differentiation into different subsets (largely unknown)
• Describe some of the signals required for Th1 cell differentiation

  IL-12: released from dendritic cells

  IFN-gamma: paracrine signalling from Th1 cells
• Describe some examples of signal 3 for Th2 cell differentiation

  IL-4: released from Th2 cells

  Number of cytokines from epithelial cells, such as thymic stromal lymphoprotein (TSLP)
• Describe cross-regulation of the two CD4+ T cell subsets

  Th1 and Th2 subsets can cross regulate each other

  • Th1 cells down regulate production of Th2 cells by the secretion of IFN-gamma
  • Th2 cells down regulate the production of Th1 cells by the secretion of IL-4

  This regulation allows the immune responses to become polarised towards either Th1 or Th2 dominated responses, which helps specialise the response to a specific pathogen.
• Describe the ‘newer’ CD4+ T cell subsets

  Th17 cells: thought to be involved in the regulation of immune responses at epithelial surfaces; in particular, the lung and intestine. Primarily characterised by the secretion of IL-17.

  T follicular helper cells: acquire a specific receptor so they can migrate to the germinal centres of the lymph nodes and support B cells in producing antibody.

  Regulatory T cells (Tregs): maintain self-tolerance by assisting in the killing of self-harmful T cells.
• Describe the signal 3 for Th17 differentiation and their action

  TGF-beta, IL-6 and IL-1 drive formation of the Th17 subset. These cells are important for fighting some fungal and bacterial infections. However, they are implicated in some autoimmune diseases due to production of proinflammatory cytokines, such as IL-17, IL-21 and IL-22
• Describe the two ways in which Tregs are formed

  1. Natural/thymic Tregs: made in the thymus as a part of normal T cell development
  2. Induced or peripheral Tregs: made in peripheral tissues or organs from naive CD4+ T cells, induced by signalling from IL-2 and TGF-beta.
• Describe the different actions of Tregs

  Inhibit harmful T cells in multiple different ways:

  • anti-inflammatory cytokines
  • outcompete effector T cells for resources
  • kill self-reactive T cells

  Lack of Tregs can lead to devastating autoimmune diseases
• Describe T cell plasticity

  T cells can become other subsets, which may allow more rapid response to different infections.