Pharmacy 310 Cell-Mediated Immunity PDF

Pharmacy 310 Cell-Mediated Immunity Dr. Michael R. Doschak Professor Faculty of Pharmacy & Pharmaceutical Sciences University of Alberta Email: [email protected]  Lecture Overview T-cell Receptor Antigen processing a...

Pharmacy 310 Cell-Mediated Immunity Dr. Michael R. Doschak Professor Faculty of Pharmacy & Pharmaceutical Sciences University of Alberta Email: [email protected]  Lecture Overview T-cell Receptor Antigen processing and MHC-Restricted presentation T-cell Activation and effector functions  T-Cell Receptor Lymphocytes (B-cells and T-cells) are derived from the same lineage B-cells express surface Immunoglobulin (BCR) T-cells express the T-cell receptor (TCR) TCR have similar structure to Ig: – 2 polypeptide chains (disulfide-linked): α-chain and β-chain (only 1 binding site) – Variable (V) and Constant (C) regions – Express unique V-region by gene rearrangement Figure 3-1 part 1 of 2 Figure 3-1 part 2 of 2  TCR interacts with the MHC (Major Histocompatability Complex) We know that Ig/Aby will bind a wide range of Antigenic epitopes – Proteins, carbohydrates, lipids – Surface of organisms, soluble toxins TCR recognize mainly peptide antigens, bound to (& presented by) MHC molecules  TCR interacts with the MHC (Major Histocompatability Complex) MHC molecules are found on the surfaces of every cell in our body (except erythrocytes) There is a diverse variation in MHC molecules in the human population MHC incompatability is the primary cause of tissue graft rejection and graft-versus-host disease  TCR Diversity Genes encoding α- and β-chains are fragmented in the germline configuration Located on chromosomes 14 and 7 respectively (Ig genes on chromosomes 14H, 2κ and 22λ) Gene segments rearranged by RAG enzyme complex to produce functional gene (and TCR with high monospecificity) ORGANIZATION AND REARRANGEMENT OF TCR GENES Figure 3-3  TCR and Accessory Proteins TCR α- and β-chains assemble in endoplasmic reticulum Associates with 4 membrane proteins, termed the CD3 complex (Chrm 11 & 1) – Gamma (γ) – Delta (δ) – Epsilon (ε) – Zeta (ζ, Chrm 1) CD3 complex facilitates TCR signaling function TCR Complex Figure 3-6  Second TCR ? There is a 2nd type of TCR (γ:δ T-cells) Composed of 2 different protein chains to α:β TCR γ:δ T-cells ( Macrophage > B-cell Professional Ag Presenting Cells (APCs) Figure 6-10 Dendritic Cell (DC) present MHC class II-bound Ag to T-Lymphocytes (L) in the Lymph Node Figure 6-11 `  Immature vs. Mature APCs Immature APCs express few MHC and B7 co-stimulatory molecules Innate immune response surface receptors are present on APCs (recognize microbial surface components) Induce B7 expression and MHC upregulation B7 ligand on APC triggers CD28 receptors on T-cells Figure 6-12 Immature APCs express few MHC and B7 co-stimulatory molecules Macrophages Figure 6-13  B-cells Figure 6-14 part 1 of 2  B-cells Figure 6-14 part 2 of 2  T-cell Activation by APCs Requires signals from the Ag/TCR + a co- stimulatory receptor (CD28) Activated T-cells then synthesize & secrete IL-2 (for autocrine and/or paracrine action) Induces T-cell proliferation & differentiation Ag recognition in absence of co-stimulation often leads to non-responsive state termed “anergy” T-cell Activation (by IL-2) Figure 6-18 T-cell “Anergy” (non-responsiveness) Figure 6-19  Inhibition of T-cell Activation T-cell activation requires signals via the Ag/TCR and a co-stimulatory receptor (CD28) that binds B7 ligand CTLA4 is an additional B7-binding receptor upregulated by activated T-cells CTLA4 is structurally similar to CD28, but binds B7 twenty times more strongly CTLA4 binding of B7 inhibits activation and proliferation of T-cells  Helper T-cell Activation by APCs Upon activation, CD4 T-cells can acquire different “helper” functions – CD4 TH1-cells (macrophage activation) – CD4 TH2-cells (B-cell activation & Aby) Figure 6-20  Cytotoxic T-cell Activation Dendritic cells and THcells activate CD8 T- cells into cytotoxic effector cells – Driven by autocrine IL-2, co-stimulatory, or paracrine IL-2 (secreted by an adjacent cell) – CD8 cells “program” the apoptosis of target cells (through membrane-bound FAS-ligand [TNF-family activator of caspase enzymes]) – Also release lytic granules (perforins and granzymes)  AUTOCRINE CD8 T-cell Activation Figure 6-22 part 1 of 3  CO-STIMULATORY CD8 T-cell Activation Figure 6-22 part 2 of 3  PARACRINE CD8 T-cell Activation Figure 6-22 part 3 of 3 CD8 Cytotoxic T-cell Mediated Apoptosis Figure 6-28 CD8 Cytotoxic T-cell Mediated Apoptosis Figure 6-30  EFFECTOR T-CELLS PRODUCE DISTINCT SETS OF EFFECTOR MOLECULES Figure 6-26  Resource Materials Parham P: The Immune System, 2/3/4 Edns., Garland Science, New York, 2005. © Copyrighted material contained herein is reproduced under ss. 29-29.4 of the Canadian Copyright Act. This document is available for your individual use; further distribution may infringe copyright.