Lecture 11 - CD4 T cell subsets (Th1 & Th2)

• Main subsets of CD4 T cells

  • Th1 cell
  • Th2 cell
  • Th17 cell
  • Treg cell
• Th1 cell


  • Induces type 1 responses to protect against intracellular pathogens such as bacteria, viruses and protozoa
• Th2 cell

  • Involved in type 2 responses to fight infections by parasites such as helminths
  • Recruits eosinophils, basophils and mast cells to the sites of infections
• Th17 cell


  • Mediates type 3 responses for the clearance of extracellular bacteria and fungi
  • Orchestrates sustained neutrophil recruitment and induction of antimicrobial peptide production by epithelial cells of barrier tissues such as intestines, lungs and skin
• Treg cell


  • Critical for the preservation of immune tolerance and prevention of autoimmune diseases
• Signal 3

  Polarising cytokines produced by innate immune cells, such as dendritic cells (DCs) and innate lymphoid cells (ILCs), in response to pathogen recognition
• Th2 differentiation

  Signal 3 is produced by parasitic worms causing tissue damage, which activates ILC2 to produce IL-4
• The production of polarising cytokines, or signal 3, is a critical step in the differentiation of CD4 T cell subsets, leading to the activation of distinct intracellular signaling pathways and the promotion of effector functions specific to each subset
• The differentiation of CD4 T cells into Th1, Th2, Th17 and Treg subsets is driven by the unique signal 3 cytokines produced in response to different types of pathogens, such as bacteria, viruses, parasitic worms, fungi and protozoa
• Th1 Induction

  1. Signal 3 for Th1 differentiation is induced by microbial pathogen-associated molecular patterns (PAMPs) stimulating dendritic cells (DCs) to produce interleukin-12 (IL-12)

  2. IL-12 acts as the polarising cytokine for Th1 differentiation, supported by type 1 innate lymphoid cells (ILC1) derived interferon gamma

  3. The IL-12 receptor on naive CD4 T cells activates Janus kinases (JAKs), signal transducers and activators of transcription factor STAT4, leading to the expression of T-bet, a lineage-specific transcription factor for Th1 cells

  4. The signaling pathway involves IL-12 binding to its receptor on the T cell membrane, leading to JAKs phosphorylating STAT4, which then translocates into the nucleus to promote the expression of Th1-specific genes and the production of interferon gamma, the signature cytokine of Th1 cells
• Th2 Induction

  1. Signal 3 for Th2 differentiation is induced by parasitic worms causing tissue damage, which activates innate lymphoid cells type 2 (ILC2) to produce interleukin-4 (IL-4) and other cytokines

  2. IL-4 acts as the polarising cytokine for Th2 differentiation, binding to its receptor on naive CD4 T cells and activating JAKs and STAT6, leading to the expression of GATA3, a lineage-specific transcription factor for Th2 cells

  3. The signaling pathway involves IL-4 binding to its receptor on the T cell membrane, leading to JAKs phosphorylating STAT6, which then translocates into the nucleus to promote the expression of Th2-specific genes and the production of IL-4 and IL-5, the signature cytokines of Th2 cells
• Pathogens Th1 cells are effective against


  • Intracellular pathogens such as viruses and bacteria
• Pathogens Th2 cells are effective against

  • Extracellular pathogens such as helminthic parasites, fungi and protozoa
• Cytokines produced by Th1 cells

  • Interferon gamma, IL-2 and TNF-alpha
• Cytokines produced by Th2 cells

  • IL-4, IL-5 and IL-13
• How Th1 and Th2 cells help B cell class switching

  1. Th1 cells, through the production of interferon gamma, induce B cells to class switch to IgG2a

  2. Th2 cells, through the production of IL-4, induce B cells to class switch to IgG1 and IgE

  3. The class-switched antibodies play specific roles in immune responses, with IgG2a being involved in opsonisation and complement activation, IgG1 being involved in neutralisation and opsonisation, and IgE being involved in defense against parasites through the release of toxic granules by eosinophils and mast cells

  4. The process of B cell class switching is essential for the generation of a diverse range of antibody isotypes, each with distinct effector functions, to effectively combat different types of pathogens, including viruses, bacteria, parasites, and fungi
• How Th1 cells help macrophage activation

  1. Th1 cells help activate macrophages by expressing CD40 ligand and secreting interferon gamma

  2. The expression of CD40L by Th1 cells binds to CD40 on the macrophage surface

  3. Once activated, the macrophage can kill the microbes it contains by fusing lysosomes with phagosomes, producing oxygen radicals and nitric oxide, which are highly toxic to the microbes

  4. Th1 cells also help activate dendritic cells at sites of infection, increasing their production of MHC class II proteins, CD80 and CD86 costimulatory molecules and various cytokines, especially IL-12, making them more effective at stimulating helper T cells to differentiate into Th1 effector cells

  5. This creates a positive feedback loop that increases the production of Th1 cells and the activation of macrophages
• How CD4 T cells help CD8 T cell responses

  1. Activated CD4 T cells "license" dendritic cells to fully activate CD8 T cells by inducing the expression of new costimulatory molecules (CD137L)

  2. Activated CD4 T cells induce the expression of new costimulatory molecules on dendritic cells, which are essential for the activation of CD8 T cells

  3. Activated CD4 T cells produce IL-2, which plays a crucial role in the proliferation and activation of CD8 T cells

  4. The presence of activated CD4 T cells enhances the activation of CD8 T cells, leading to stronger cytotoxic T lymphocyte (CTL) activation

  5. CD4 T cells are required for the secondary expansion and memory in CD8 T lymphocytes, indicating their crucial role in sustaining and enhancing the CD8 T cell responses