PBS 803 Class 7 T lymphocyte biology I

PBS 803 - Class #7 T lymphocyte biology I Suggested Reading: Abbas pages 103 -121 Flaherty pages 50 -52 September 14 th, 2016 Parham Fig. 9. 10, activated T-cell providing stimulation to B-cell

Learning Objectives for Class #7 part I ·Explain how CDRs of TCR determine MHC restriction with regard to binding specificities for both antigen and MHC isotype · List several examples of unique features associated with γ: δ T-cells · Discuss the steps involved in lymphocyte activation: protein synthesis, proliferation, differentiation, homeostasis and memory cell formation. · Describe the functional significance and cellular distribution of the following: CD 3, CD 4, CD 8, CD 28, CD 40, TCR, BCR, Ig domain, MHC Class II · Describe additional components associated with T-cell activation not listed in previous objective: B 7: CD 28, B 7: CTLA-4, ITAM, ITIM, zeta chain (ζ), adhesion molecules · Explain the two-signal model of T cell activation and the role of inflammatory cytokines and the costimulatory CD 28 molecule

Learning Objectives for Class #7 part 2 · Explain the importance of IL-2 in activation of TH cells through autocrine and paracrine mechanisms · Illustrate the mechanism of superantigen activation of T cells and explain significance · List several examples of biochemical events triggered in T cells by antigen recognition · Describe the mechanism of action of Cyclosporine and Rapamycin · Explain the cross-presentation of antigen by dendritic cells to CTLs and explain its significance in coordinating the activation of TH cells and CTLs · Explain the importance of CD 40 L-CD 40 interactions with the activation of the cell-mediated and humoral immune branches by TH cells · Describe different CD 4+ TH cells that can be produced in secondary lymphoid organs

Highly polymorphic MHC isotypes result in transplantation rejection, polymorphic residues of MHC can be recognized as foreign by lymphocytes Isotype – protein products of different MHC genes (e. g. HLA-A vs. HLA-B isotypes) Allotype (or isoform) used to designate individual MHC molecules produced by individual alleles e. g. , there are thousands of alleles of HLA-A isotype in human population, therefore there are thousands of HLA-A allotypes (or isoforms) in the population Parham Figure 5 -28

MHC restriction: TCRs are specific for both peptide and MHC allotypes as determined by CDRs of TCR CDR- complementarity-determining regions, regions within hypervariable regions of TCRs, BCRs and Igs that determine epitope binding site Abbas Fig. 3. 1 Flaherty Fig. 6. 3

Gene rearrangement of T cell receptor genes Flaherty Fig. 6. 4

Ability to utilize combinatorial diversity in generating TCRs and BCRs critical step in evolution of adaptive immune system FYI: estimated that process began ~400 million years ago, dinosaurs went extinct ~65 million years ago Parham Fig. 5. 5

Variable regions of both α: β and γ: δ TCRs are produced by combinatorial & junctional diversity Similar to what was discussed for BCRs in Chapter 3 Distinct properties of γ: δ T-cells -less diversity in receptors generated -predominantly in tissues (e. g. , MALT) α: β cells are most commonly in blood or secondary lymphoid tissues Parham Fig. 5. 7 -γ: δ T-cells can recognize peptides independent of MHC, can recognize non-peptide antigens

Types of microbes combated by cellular immunity in addition to transformed and damaged cells Abbas Fig. 5. 1

Induction and effector phases of cell-mediated immunity Abbas Fig. 5. 2

Steps in the activation of T lymphocytes Abbas Fig. 5. 3

Properties of major cytokines produced by TH cells applies generally to T cell cytokines Abbas Fourth Edition Fig. 5. 10

Molecules involved in T cell activation Abbas Fig. 5. 4 A

Molecules involved in T cell activation Abbas Fig. 5. 4

The TCR complex is required for T-cell activation TCR by itself has no intrinsic activity Notice the Ig structural domains containing disulfide bonds. Ig domains are also found in BCRs, secreted Igs and other proteins Parham Fig. 6. 5

Antigen recognition and signal transduction during T cell activation Abbas Fig. 5. 5

Role of costimulation in T cell activation Abbas Fig. 5. 6

Proteins of the B 7 and CD 28 families Abbas Fig. 5. 7

Mechanism of the inhibitory protein CTLA-4 Flaherty Fig. 6. 6

Many therapeutics target interactions between APCs and T-cells For example, agents that block B 7: CD 28 signaling used in the treatment of rheumatoid arthritis Conversely, inhibition of CTLA-4 can be used to strengthen signal, used for patients with cancer Notice that CD 3 is a common target of monoclonal antibodies designed to inhibit T-cells. Flaherty Table 6. 1

Activation of CD 8+ cells Activation of naïve CTLs typically requires assistance from CD 4+ TH cells, through cross-presentation (cross-priming), though this rule is not absolute Abbas Fig. 5. 8

Production of proteins prior to cell division in activated lymphocyte (IL-2, high affinity IL-2 receptor and CD 40 L) Abbas Fig. 5. 9 A

Production of proteins prior to cell division in activated lymphocyte Abbas Fig. 5. 9

Signal transduction pathways in T lymphocytes Cyclosporines and Rapamycin are immunosuppressants that target this pathway. Abbas Fig. 5. 10

Expression and decline of T cell responses Abbas Fig. 5. 11

Expansion and decline of T cell responses. Abbas Fig. 5. 12

CD 40 L-CD 40 signaling assists activation of cell-mediated and humoral immunity by TH cells Abbas Fig. 5. 13

Superantigens stimulate abnormally large numbers of T cells, can cause systemic inflammation resulting in shock, death. notice that superantigens crosslink the complex outside of antigen-binding cleft Up to 20 -25% of TH cells can be stimulated in severe cases, (normal antigen responses stimulate less than 0. 01% of TH lymphoctyes) Superantigens are associated with some Gram positive bacterial species Flaherty Fig. 6. 7