T-Cell Activation, Differentiation & Memory

T-Cell Activation, Differentiation & Memory

1. 3 Signals Required for T-Cell Activation

   • 1. TCR Signaling
     • 1: TCR:CD3 Binds MHC Peptide
       • CD3 and CD4/8 are stabilizing co-receptors
     • 2. TCR Relocates to lipid raft and forms the Immunological Synapse
       • ICAM:APC and Integrins(LFA):Tcell anchor the cells while the TCR complexes form
     • 3. CD4 or CD8 clusters with TCRs to bind MHC molecules on APCs
       • Co-Receptor Binding
   • 2. Costimulatory Interaction
     • 4. CD28(T-cell) binds B7 family signaling molecule on APC
       • CTLA-4 is expressed on activated T-cells and negatively regulates T-cell activation
         • CTLA-4 competes with CD28 for the binding sites on B7
       • CD28 is expressed by both resting and activated T-cells
       • B7 is expressed on professional APCs
   • 3. Cytokine Signaling
     • 5. p56 interacts with CD4/8 and TCR/CD3 complex at the TCR:CD3 cytoplasmic tail
       • p56LCK is a cytoplasmic membrane kinase
       • 6. p56LCK induces ITAM signaling
         • Induces Tx of cytokines: NFAT, NF-kB, and AP-1
         • ITAM: immunoreceptor tyrosine-based activation motif

2. Clonal Anergy

   • T-cells are rendered inactive if missing co-stimulatory signals
     • Activation of anergic genes
     • Helps prevent auto-immunity by forcing specificity
   • Irreversible
   • Can be induced by neg. regs like CTLA-4
     • Fab anti-CD28 prevents CD28 binding to CD80/86 (B7 family)
   • Can cause T-Cell exhaustion after prolonged activation
     • So, we have T-cells, and they survive but do not function?
   • Occurs in the lymph nodes

3. Superantigens: Viral or bacterial antigens that can bind TCR B-chains and MHC II a-chains

   • Antigen specificity does not matter here!
     • Independent of Antigen processing and presentation
   • Stimulation is polyclonal and leads to overproduction of cytokines & systemic toxicity
   • Binds to the MHC a chain and TCR VB

4. T-cell Differentiation

   • IL-2 autocrine signaling induces clonal expansion
     • Results in mostly effector cells and few memory cells
       • Memory cells go into quiescence

5. Helper T cell Types

   • TH2
     • Responds to extracellular pathogens
       • Signals B-cells to secrete Ig
       • Assists Humoral immunity
   • TH1
     • Responds to intracellular pathogens
       • Signals MP to kill bacteria
       • Activates Cytotoxic T-cells
       • Assists with Cell-Mediated Immunity

6. Activation typically occurs with proffesional APC in a secondary lymphoid organ, but can occur anywhere due to all nucleated cells containing MHC Class I molecules

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