Lecture 2 Week 3: T Cells

Lecture 2 Week 3: T Cells

1. TCR variable and constant regions

   • beta chains: variable region comprised of protein segments encoded by variable, diversity and joining genes
   • alpha chain: variable region comprised of variable and joining gene products

2. Stages of T cell maturation

   • Immature T cells move from bone marrow to the thymus
   • They express
     • Pre-TCR
     • TCR (Antigen binding)
     • Undergo selection
     • Change surface markers (i.e. CD4 and CD8)

3. Positive selection of T cells: MHC restriction

   • Positively seleccted for low affinity recognition of MHC
   • Lack of MHC binding results in no signals via TCR - apoptosis
   • Affinity for either MHC Class I or II effects type i.e. helper CTL

4. Central tolerance: negative selection

   • MHC/peptide complexes in thymus contain self-antigens
   • Immature thymic T ccells that display high affinity binding for these MHC/self antigen complexes are induced to undergo apoptosis
   • Acts to prevent autoreactive T cells

5. Activation of T cells by APCs

   • APCS are required to present antigen to T cells
   • Dendritic cells (also macs and neutrophils) carry antigens to lymph nodes from sites of infection (B cells also present)
   • Presentation to naive mature T cells activate these to become effector cells
     • T helper cells (CD4+)
     • T cytotoxic cells (CD8+)

6. Cross presentation of antigen by APCS

   • APCs can cross present phagocytoses viral (or bacterial) antigens to T cells by combining them in MHC Class I complex
   • Important mechanism for priming CD 8+ responses
   • APC may simultaneously present peptides complexed with MHC I and II

7. Loading of peptides in MHC complexes

   • Class I used for cytosolic proteins
     • Self peptides
     • Viral peptides
   • Class II used for
     • Phagocytosed/endocytosed peptides

8. T cell activation

   • Induction of cytokines
   • Clonal expansion
   • Differentiation to effector cells (I.e. T helper or CTLs)
   • Generation of memory subsets

9. Co-stimulation of T cells

   • Co-stimulation is an important regulator of T cell activation
   • Inappropriate presentation of MHC/antigen complex will not activate T cell (i.e. anergy)
   • Co-stimulation includes ligand/receptor and cytokine/receptor interactions

10. Lymphocyte activation events are often complex

    • Multiple interactions may occur which generate activated effector T cells in an immune response
    • High level of interactivity amongst the various immune cells

11. Signal transduction via TCR: the immunological synapse

    • Upon TCR binding of MHC/antigen complex, other T cell membrane receptors/proteins are recruited to the site
      • i..e CD3 and Z chains, CD4 or CD8
    • Close proximity of LCk to tyrosines results in phosphorylation to phosphotyrosines

12. Signal transduction via the TCR

    • Signal transduction results in activation of transcription factors
    • Results in induction of cell division (i.e. clonal expansion), differentiation (i.e. up-regulation of surface proteins, RNA synthesis (i.e. cytokine production)

13. Affinity maturation

    • During clonal expansion in germinal centers
    • Complementary determining regions (CDR) have high rate of mutations
    • Results in B cell progeny displaying surface Ig of varying affinity for antigen