Antigen Capture and Presentation to Lymphocytes PDF

#Immunology Antigen Capture and Presentation to Lymphocytes: What Lymphocytes See  Main Study Points ØHow do rare naive lymphocytes specific find microbe specifically? ØHow do different types of T cells recognize microbes in different cellular compartments? ...

#Immunology Antigen Capture and Presentation to Lymphocytes: What Lymphocytes See  Main Study Points ØHow do rare naive lymphocytes specific find microbe specifically? ØHow do different types of T cells recognize microbes in different cellular compartments?  Antigens Recognized by T-Lymphocytes qThe majority of T lymphocytes recognize pep>de an>gens bound to and displayed by the MHC molecules of an>gen-presen>ng cells (APCs). Capture and Display of Microbial Antigens Antigen Uptake, Maturation and Migration of Dendritic Cells to Activate T- Cells ØAll DCs express PRRs on their surface (e.g TLRs , C-type lec>n receptors (CLRs). ØDendri>c cells mature: upon pathogen recogni>on or in response TNF,IL1. ØMatura>on markers include: vExpression of cos>mulatory molecules such as CD40, CD80 and CD86. vLoss of adhesiveness vExpression of chemokine receptor (CCR7). vDC migra>on to lymphoid organs to present the processed an>gens for T cell ac>va>on. v Raise in the levels of major histocompa>bility complex (MHC) class II expression.  Major Histocompatibility Complex qMHC(HLA):Gene>c locus ØDetermine the acceptance or rejec>on of >ssue graYs exchanged between individuals. ØCode for membrane proteins on APCs that display pep>de an>gens for recogni>on by T lymphocytes. ØCode for Transporter associated pep>de(TAP): responsible for intracellular transloca0on of pep0des across the membrane of the ER. ØMHC III: contain genes for complement C2,C4,factor B and cytokines.  Genes Coding for MHC Molecules The HLA system is the most polymorphic gene system in humans. Thousands of alleles – alternate forms of a gene that code for a slightly different variety of the same product – are found: More than 4,600 different HLA-A alleles, 5,500 HLA-B alleles, and 4,300 HLA-C alleles Each person has two HLA alleles of each type; linked genes are inherited (haplotype)  Structure of MHC Molecules qClass I MHC Molecules: ØConsists of α chain non covalently associated with β2- microglobulin. Øα domain consist of two walls and pep>de binding cleY. Ø Pep>de binding cleY floor contains amino acids that bind pep>des to display to T-lymphocytes. ØThe wall make contact with TCR. vMHC-I polymorphism occurs mostly in the α chain amino acid residue in the floor. Øα3 domain is invariant and contains a site that binds the CD8 T cell coreceptor. qClass II MHC Molecules: ØConsists of two transmembrane chains, α2 and β2. ØThe amino-terminal regions of both chains α1 and β1 domains , contain polymorphic residues and form a cleY. Øβ2 domains contain the binding site for the CD4 T cell co- receptor.  Properties of Major Histocompatibility Complex (MHC) Molecules and Genes qLocated in the short arm of chromosome 6. qEach person inherits one of HLA class I genes(A,B,C) from each parent. q Each person inherits two of HLA class II genes(DP,DQ) encoding for α chain and the β chain from each parent. ØEach HLA allele is given a numeric designa>on :e.g:HLA-A2,B5,DR3---- etc. vOne or two for DRβ (HLA-DRB1 always present. vHLA-DRB3, HLA-DR4, or HLA-DR5) some >mes present. vOne for DRα.  Antigen Capture and Presentation to Lymphocytes vReac>ons of MHC molecule: ØMay be involved in the reac>ons of T cells to some nonpep>de an>gens, such as small molecules and metal ions. vClass I MHC proteins (A, B, and C) present intracellular an>gens origina>ng from viruses or tumors(in the cytosol) to cytotoxic T lymphocytes vMHC class II proteins (DR, DQ, and DP) present extracellular an>gens(processed in endosomes) to T-helper cells. vA single T cell need to see a pep>de displayed by only as few as 0.1% to 1% of the approximately 105 MHC molecules on the surface of an APC. vMHC molecules are unable to discriminate between self and foreign an>gens ØT cells specific for self an>gens are either killed or inac>vated.  Clinical Significance of MHC Important in 0ssue transplant procedures MHC classes I and II can induce graQ rejec0on. Certain HLA types appear to play a role in development of autoimmune diseases.  Associa7on of HLA Alleles and Disease DISEASE SYMPTOMS HLA ALLELE STRENGTH OF ASSOCIATION Ankylosing spondyli0s Inflamma0on of the vertebrae of the B27 +++ spine Celiac disease Diarrhea, weight loss, intolerance to DQ2 +++ gluten DQ8 + Rheumatoid arthri0s Inflamma0on of mul0ple joints DR4 + Type 1 diabetes Increase in blood glucose because of DQ8 ++ destruc0on of insulin-producing cells DQ2 + +++ = very strong associa0on, ++ = strong associa0on, + = clear associa0on, – = nega0ve associa0on.  Class I MHC Pathway of Processing of Cytosolic Antigens qUbiqui>n-proteasome pathway: vCytosolic Proteins are unfolded and covalently tagged with ubiqui>n pep>de. vUnfolded proteins are threaded through proteasome which degrade them to pep>des. ØTransporter associated with an>gen processing (TAP): vTransporter molecule in the ER membrane binds proteasome-generated pep>des on the ER membrane, then ac>vely pumps them into the interior of the ER. ØChaperone: v Stabilizes newly synthesized class I MHC molecule. ØTapasin : vStabilizes MHC-I by ahachment to TAP. Tc Recognize and Destroy Target Cells CD8+ Tc bind to the an0gen-MHC Class I complex on the target cell surface. Tc release enzymes that destroy the target cell.  Class II Major Histocompatibility Complex Pathway of processing of Internalized Vesicular Antigens ØExtracellular microbes or proteins are ingested by phagocytosis or receptor mediated endocytosis. vB lymphocytes internalize proteins that specifically bind to the cells’ an>gen receptors. ØProteins enter acidic vesicles(endosomes or phagosomes) which fuse with lysosomes and broken by proteoly>c enzymes. ØInvariant chain (Ii): vBinds Class II MHC synthesized in ER. Ø Contains class II invariant chain pep>de (CLIP) sequence. vDirects class II molecule to migrate to the endosomes and lysosomes. ØCLIP: v Binds to the pep>de-binding cleY of the class II molecule. ØHLA-DM : vClass II MHC–like protein. v Exchange CLIP with other pep>des available in the vesicles that can bind to the MHC molecule with higher affinity. Th Assist An7body Produc7on CD4+ T helper cells s0mulate B cells to divide and differen0ate into an0body-producing plasma cells.  Class I MHC-Restricted Cross-Presentation of Microbial Antigens from Infected Cells by Dendritic Cells qCross presenta>on: ØSubset of classical dendri>c cells has the ability to ingest infected host cells, dead tumor cells, microbes, and microbial and tumor an>gens. Ø Transport the an>gens into the cytosol. ØAn>gens are processed by the proteasome. ØThe an>genic pep>des enter the ER and bind to class I molecules. ØThe an>gens are displayed for recogni>on by CD8+ T lymphocytes. ØDifferen>ated CD8+ Cells into CTLs kill infected host cells or tumor cells without the need for dendri>c cells or signals other than recogni>on of an>gen. qCarried out when viruses infec>ng cells other than dendri>c cells or when tumor arise from different types of cells. Thanks  Role of MHC-Associated Antigen Presentation In Recognition of Microbial Antigens by CD8+ and CD4+ Effector T Cells qImmuno-dominant pep>des: vOnly pep>des bind to the MHC molecules in that individual can be presented for recogni>on by T cells.  Functions of Antigen Presenting Cells ØThey display pep>des for recogni>on by T cells in response to microbes. ØExpress addi>onal signals for T cell ac>va>on(B7 :C80,CD86 bind to CD28 on T-cells).  Antigen Recognition by B-Cells and Other Lymphocytes qFollicular dendri>c cells (FDCs): vPresent in the B cell–rich lymphoid follicles of lymph nodes and spleen. ØThey are not bone-marrow derived. ØDevelop from perivascular precursors of stromal cell origin that are seeded through- out the body. ØNot related to the dendri>c cells that process and present an>gens to T cells. vDisplay intact an>gens(na>ve, in a form of immune complexes) to ac>vated B cells. ØExpress receptors that bind an>gens coated with an>bodies or complement by-products such as C3b and C3d, with no role for MHC molecules. ØAc>vate B-cells and induce affinity matura>on of an>bodies.