* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Generation of ligands for the T cell receptor
Survey
Document related concepts
Lymphopoiesis wikipedia , lookup
Human leukocyte antigen wikipedia , lookup
Complement system wikipedia , lookup
Immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Adaptive immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Biochemical cascade wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Transcript
Summary of the last lecture • Features of T cell antigen recognition – – – – APC Ag processed MHC restrictions TCR ligand: Peptide + MHC • Basis for Ag presentation by MHC – Genetic basis – Polygeny – Polymorphism – Structural basis – MHC polymorphic binding pockets – Peptide anchor residues • Types of APC – Target cell – Professional APC Student Q1: What cells express MHC molecules: Class I, Class II or both, & why? • Virtually all nucleated cells express MHC Class I • Potentially infectable (e.g. by virus) as target cells (for Tc) • Thymic stromal cells express both • T cell selection –thymic education • Key immune cells express both • B cells: present Ag to Th to receive help for Ab responses • MQ: first line of defense, once activated ‘professional’ APC • DC: initiation of immune responses ‘true professional’ APC Pathways of Ag processing, Ag presentation & co-stimulations • Types of pathogens & Ags • Two classical pathways for Ag processing • Ag processing, presentation, & their clinical relevance • Cell interactions & co-operation Question: How is a TCR ligand generated? Ag processing & presentation T APC Types of pathogens 2 1 cytosol “endogenous” ER 3 Vesicles Endocytic vesicles “exogenous” Types of pathogens or antigens: • Cytosolic - “endogenous” - viruses, intracellular bacteria • Endocytic/vesicular - “exogenous” - Intra-vesicular bacteria, parasite etc. - Extra-cellular pathogens, toxins Two major subsets of T cells whose recognition of antigens are restricted by two different classes of MHC: • CD8+ T cell (cytotoxic T) - MHC Class I restricted • CD4+ T cell (T helper) - MHC Class II restricted Ag processing & presentation Endogenous/Cytosolic Tc TH I TAP II APC TAP: Transporters associated with Ag processing Exogenous Intro-vesicular Two classical pathways of Ag processing: • Endogenous (cytosolic) pathway “MHC Class I pathway” Tc cells • Exogenous (endocytic) pathway “MHC Class II pathway” Th cells (TAP) Proteasome & subunit The Class I pathway 1 2 Empty Class I molecules are unstable under physiological temperature TAP deficient (RMA-s) Normal Exogenous peptides (370C) 370C 19 - 330C Empty MHC class I molecule come out in the cold By Ljunggren HG et al. Nature (1990) 346:476-80 3 The Class II pathway Ii CLIP Functions of the Invariant Chain (Ii) • Block MHC Class II molecules from binding of peptides derived from endogenous antigens • Direct MHC Class II molecule to cellular vesicles where exogenous peptides are generated CLIP HLA-DM Cytosolic proteins proteasome peptides TAP Ag processing, presentation & their clinical relevance • Pathogen strategies for immune evasion: - prevent TAP function (HSV) - inhibit endosomal acidification (Helicobacter pylori) - retention of MHC molecules (Retroviruses) • Vaccine design: Types of immune responses: - Humoral (B) endocytic pathway - Cell-mediated (CTL) cytosolic pathway • MHC deficiencies: - Congenital MHC class II deficiency - Ir gene defects MHC deficiency Heterozygotes b A a b E a Inbred A1 A B 1 2 1 2 B1 Homozygotes b A a b E A1 B1 A1 B1 a B1 B1 A1 A1 B1 B1 Student Q2: ‘Self’ MHC restriction? T cells recognize “self” MHC The environment in which the T cells mature determines the MHC restriction of the mature T cell receptor repertoire Cell interactions & co-operations • Cell adhesion molecules • Cytokines and cytokine receptors Question: Chances of the specific T cell:APC interactions ? (1) (3) (2) Organized distribution F (B + FDC) GC + DC T: T cell area B: B cell area F: B cell follicle GC: germinal centre Question How do cells know where to go and act ? Adhesion molecules: SELECTINS - e.g. L-selectin, P-selectin, E-selectin MUCIN-LIKE MOLECULES - (Addressins) e.g. CD34 INTEGRINS - e.g. LFA-1, VLA-4 IMMUNOGLOBULIN SUPERFAMILY - e.g. CD2 (LFA-2), ICAM-1, 2, 3 T cell-endothelium interactions Lymph node cortex (3) HEV Endothelium CD34 Glycam 1 ICAMs LFA-1 L-Selectin T (1) HEV: high endothelial venue T (2) T cell:APC interactions Armed effector T cells are guided to sites of infection by newly expressed adhesion molecules Cytokines - Small pharmacologically active products of cells - Nomenclature & classification • Lymphokines: produced by lymphocytes • Interleukins: interleukin 1 - 26 (IL-1 – IL-26) interferons, TNF etc. • Monokines: produced by monocytic/phagocytes • Chemokines: CXC (IL-8), CC (DC-CK, MDC), CX3C (Fractalkine) Chemokines & Chemokine receptors Chemokine Group Examples Target cells Receptors CXC IL-8 Mig, IP-10 neutrophils activated T CXCR1, 2 CXCR3 CC MIP-3b DC-CK1, MDC naïve T naïve T DC, T, NK CCR7 ? CCR4 C & CX3C Fractalkine T, mono., neutr. CX3CR1 6-Cysteine CC 6Ckine T, B, mesangial ? ELR+ ELR- *ELR: Cysteine residues ‘Glu-Leu-Arg’ g IL-2Ra (CD25) - Cell activation marker T cell activation and proliferation (high affinity) Summary 1 Two types of pathogens/Ags: • Cytosolic - “endogenous” - viruses, intracellular bacteria • Endocytic/vesicular - “exogenous” - Intra-vesicular bacteria, parasite etc. - Extra-cellular pathogens, toxins Summary 2 Two classical pathways for Ag processing • “MHC class I pathway” CD8+ T cells (Endogenous/cytosolic, TAP-dependent pathway) • “MHC class II pathway” CD4+ T cells (Exogenous/endocytic, TAP-independent pathway) Summary 3 • A defect or defects in Ag processing or presentation may result in severe immunological consequences • Pathogens may evade host immune system by interfering with the mechanisms of Ag processing and presentation • Cells of the immune system interact in a complex network • Cell interactions and re-circulation are mediated by adhesion molecules, cytokines and cytokine receptors Summary 4 Cytokines - principles of action • Local & systemic effects • Unique receptor for each cytokine • Pleiotropic • Synergistic & autocrine fashion • Complex network – a single cell can secrete, or be susceptible to, more than one cytokine