T-Cell Development

T-Cell Development

1. HSC differentiate into immature thymocytes in the bone marrow

   • Thymocytes develop into mature T-cells in the thymus
     • Mature T-cells become activated in secondary lymphoid organs
       • T-Cell Activation, Differentiation & Memory
       • Activated T-cells perform effector functions in the periphery
     • CORTEX
       • Positive Selection
         • Establishes MHC Restriction
         • Cells start out double positive
           • Death by Neglect: no TCR interaction with Self-MHC
             • 90-96%
           • Apoptosis: High affinity TCR interaction with Self MHC
           • Positive Selection: Low-Intermediate affinity TCR interaction with self MHC
             • 2-5%
           • Co-Receptor Selection
             • Instructive Model
               • Driven by engagement signal
                 • Downregulation of 'other' coreceptor
             • Stochastic Model
               • Random event
                 • Positive Association or Apoptosis
             • Kinetic Model
               • Strength and Duration of signal
                 • Engagement signal leads to downregulation of CD8
                   • If continuous signaling occurs then CD4+
                   • If signaling interrupted, cell is rescued by IL-7 CD8+
         • Mediated by thymic stromal cells
       • Somatic recombination forms the TCR
         • Early Thymocytes are double negative
           • DN2: T-Cell Commitment
           • DN3: B-selection and proliferation
           • DN4: TCRa locus rearrangement
             • a chain may undergo multiple rearrangemnts to rescue non productive TCRs
           • DN1: TCRB locus rearrangement and proliferation
             • B chain is rearranged first and expressed with pTa chain then will rearrange and express a chain
     • MEDULLA
       • Negative Selection
         • Does this happen to the cells that are positively selected for?
         • Establishes Self-Tolerance
         • Cells are single positive
           • Clonal Deletion
             • Strong TCR Interaction with MHC/Self-Peptide
             • 2-5%
           • Mature T-cell
             • Low affinity TCR interaction with MHC/Self-peptide
           • T-regs (Regulatory T-Cells)
             • Alternative fate for autoreactive T-Cells
             • Inhibit the function of T-Cells to prevent AI
             • Express FoxP3
         • Mediated by bone marrow derived cells