Antigen Presenting Cells

1. CD4+ T cells only see antigen presented on MHCII 2. CD8+ T cells only see antigen presented on MCHI General Features 1. innate system activated cytokines + APCs T lymphocyte differentiation 2. professional antigen presenting cells present antigen to CD4s a. dendritic cells most efficient during primary response b. macrophages most efficient during secondary response c. B cells 3. antigen is presented on major histocompatibility complex (MHC) 4. all APCs require: a. MHC II b. Costimulatory molecules (B7, CD40) 5. Cells that present antigen to CD8+ T cells are called target cells because these cells are targeted for death 6. Any nucleated cell is a potential target because all nucleated cells express MHC I Dendritic cells 1. immature dendritic cells a. everywhere (in skin = Langerhans cells) b. Function: Ag capture (carry Ag from peripheral tissues to secondary lymphoid tissue) c. High Fc R, low MHC II and costimulatory molecules d. Express CD4, chemokine receptors CCR5, CXCR4: receptors for HIV 2. mature dendritic cells a. secondary lymphoid tissue b. Function: Ag presentation and cytokine secretion (IL-12) c. High MCHII and costimulatory molecules 3. present antigen and activate T cells Macrophages 1. Express CD4, chemokine receptors CCR5, CXCR4: receptors for HIV B cells 1. recognize antigen via membrane antibody receptor 2. best APC when antigen is low 3. antigen is taken up with receptor into an endosome

Antigen Presenting Molecules

1. Two types: a. class I MHC molecules 1. all nucleated cells 2. encoded by 3 loci = A, B, C 3. b. class II MHC molecules 1. all professional APCs 2. encoded by a D locus subdivided into: DP, DQ, DR 2. In humans, MHC = human leukocyte antigen (HLA) 3. polymorphism: genes encoding each MHC locus are present in multiple forms a. characteristic of both class I and II MCH

Antigen Presenting Molecule: Class I MHC Molecules

Role of class I MHC molecules and class I MHC restriction 1. antigen + MHC I recognized by CD8s 2. CD8s only recognize viruses or other cytosolic pathogens presented on MHC I = class I MHC restriction Structure of class I MHC 1. transmembrane polymorphic polypeptide heavy chain binds antigen 10 aas long 2. nonpolymorphic 2-microglobulin does not bind antigen Nomenclature and codominant expression of class I MHC molecules 1. class I MHC molecules are codominantly expressed: inherit a copy from each parent (6 class I MHC) Antigen processing 1. 2. 3. 4. 5. 6. free microorganisms in cytoplasm are degraded by proteosome peptide fragments bind to transporter of antigen processing (TAP) TAP transports peptides from cytosol to ER peptides bind MHC I complexes released in vesicles from Golgi vesicles fuse with plasma membrane and are displayed

Class I MHC molecules and viral evasion of immune defenses 1. Herpes simplex virus (HSV) a. hides in neurons that have little MHC I b. inhibits TAP in non-neuronal tissues

2. Epstein Barr virus (EBV) a. latent infection in B cells b. inhibits proteosome 3. Cytomegalovirus (CMV) a. takes class I MHC from ER back into cytoplasm b. class I MHC are degraded by proteosome

Antigen Presenting Molecules: Class II MHC Molecules

Role of class II MHC molecules and class II MHC restriction 1. MHC II present antigen to CD4s 2. class II MHC restriction 3. class II MHC activate CD4s which in turn secrete cytokines Structure of class II MHC molecules 1. heterodimer of two transmembrane polymorphic polypeptide chains 2. binds antigen 15-10 aas in length 3. invariant chain (Ii) binds to class II MHC in ER a. blocks binding of excess peptide b. direct transport of MHC II through Golgi Nomenclature and codominant expression of class II MHC molecules 1. codominant expression: one copy inherited from each parent 2. six class II MHC Processing of microorganisms and association with class II MHC molecules 1. 2. 3. 4. 5. 6. 7. 8. extracellular microorganisms are endocytozed by APCs endosome fuses with lysosomes endosome with pathogen fuses with another endosome with class II MHC Ii chain is degraded by lysosomal enzymes peptide binds to class II MHC chimeric endosome fuses with cell membrane and is displayed recognition by CD 4s secretion of cytokines by CD4s

Disease association with class I and class II MHC expression 1. HLA-B27 ankylosing spondylitis in Caucasian males 2. HLA-DR3, HLA-DR4 type 1 diabetes

Antigen Presenting Molecules: CD1 molecules Nomenclature and structure 1. similar to class I have 2-microglobulin 2. no polymorphism like class I Tissue distribution and function 1. tissue distribution similar to MHC II 2. present lipid and/or glycolipid antigens to CD4+ and with mycobacterial infection T cells specially