5.3 T cell activation and differentiation

T cell activation is a crucial process in the immune response. It involves a two-signal model where antigen recognition and co-stimulation work together to fully activate T cells, while mechanisms like anergy prevent unwanted responses.

Once activated, T cells undergo differentiation into various subsets with specific functions. This process is guided by cytokines and transcription factors, resulting in effector and memory T cells that play key roles in fighting infections and maintaining immunity.

T Cell Activation

Two-signal model of T cell activation

• Signal 1: Antigen recognition through TCR binding to peptide-MHC complex on APC provides specificity for immune response
• Signal 2: Co-stimulation via CD28 on T cell binding to CD80/CD86 on APC enables full T cell activation and proliferation
• Antigen presentation by professional APCs (dendritic cells, macrophages, B cells) presents peptides to CD8+ T cells via MHC class I and CD4+ T cells via MHC class II
• Co-stimulatory molecules include CD40-CD40L, ICOS-ICOSL, and 4-1BB-4-1BBL interactions amplify activation signals

T cell anergy and peripheral tolerance

• T cell anergy induces functional unresponsiveness when T cells receive Signal 1 without Signal 2 preventing autoimmune responses
• Anergy induction mechanisms involve lack of co-stimulation or engagement of inhibitory receptors (CTLA-4, PD-1)
• Peripheral tolerance importance lies in preventing self-reactive T cell activation escaping central tolerance maintaining immune homeostasis complementing other tolerance mechanisms (regulatory T cells)

T cell differentiation into subsets

• Clonal expansion drives rapid proliferation of activated T cells through IL-2 production and signaling
• Effector T cell differentiation produces CD4+ T helper subsets (Th1, Th2, Th17, Tfh) and CD8+ cytotoxic T lymphocytes (CTLs)
• Memory T cell formation generates central memory (TCM), effector memory (TEM), and tissue-resident memory (TRM) cells
• Differentiation factors include TCR signaling strength and duration, cytokine environment, and transcription factor expression

Cytokines in T cell function

• Th1 differentiation utilizes IL-12 and IFN-γ, activating T-bet and STAT4 transcription factors for cell-mediated immunity and intracellular pathogen defense
• Th2 differentiation relies on IL-4, activating GATA3 and STAT6 transcription factors for humoral immunity, parasite defense, and allergy responses
• Th17 differentiation requires TGF-β, IL-6, and IL-23, activating RORγt and STAT3 transcription factors for mucosal immunity and neutrophil recruitment
• Tfh differentiation depends on IL-21, activating Bcl-6 transcription factor for B cell help and germinal center formation
• CTL differentiation uses IL-2 and IFN-γ, activating Eomesodermin and T-bet transcription factors for cytotoxicity and virus-infected cell elimination