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October 21, 2004 IMMUNITY MHC ADAPTIVE INNATE EFFECTOR SYSTEMS Fc Receptors Complement CELL MEDIATED TCR HUMORAL ANTIBODIES ANTIGENS BCR Soluble Ab RECEPTORS EFFECTORS Cells Molecules The Major Histocompatibility complex (MHC) HLA in human H-2 in mice The main barrier to organ transplatation Role of the MHC: Present Ag to T cells B cellss interact with free native Ag in solution. T cells only interact with Ag at cell surfaces and the requirement for co-recognition of Ag and MHC ensures that this happens Class I MHC Cell surface glycoprotein Two chains: 45 kD transmembrane chain with carbohydrate Non-covalently associated 13kD -2 microglobulin -2 is not a transmembrane protein Class II MHC Found on a restricted number of cells Usually B, M, dendritic cells, sometimes T Antigen presenting cells Transmembrane chain of 32 kD Transmembrane chain of 27 kD Within the cell it is associated with the invariant chain, Ii Class II MHC Found on a restricted number of cells Usually B, M, dendritic cells, sometimes T Antigen presenting cells Transmembrane chain of 32 kD Transmembrane chain of 27 kD Within the cell it is associated with the invariant chain, Ii Note contact of TCR with peptide and MHC moleculeMHC RESTRICTION Class I and Class II both Function to Present Antigen Different Roles Class I displays fragments of protein synthesized inside cell If peptide is foreign, cell is killed by CD8 T cells Expressed on all nucleated cells Class II functions to display fragments of proteins from outside the cell Expressed only by proliferating APC If peptide is foreign, CD4 T cells are activated Help B cells Inflammation Genes of the MHC HLA in hum an Class I -chain genes: HLA-A, -B, -C -2 microglobulin encoded outside MHC Class II - three pairs of - and - chain genes HLA-DR: HLA-DP: HLA-DQ: TAP-1 and TAP-2 encode peptide transporter LMP encodes com ponents of the proteasome DM resem bles class II; catalyzes peptide binding to MHC Class III - other genes in MHC, som e important in im m une function C2, C4, Factor B, TNF- , TNF- Variability Tremendous polymorphism Germline encoded Extensive variation within species For some MHC loci there are more 100 alleles P o P Polymorphism concentrated in amino acids lining the binding pocket For Class II the polymorphisms are also concentrated in the binding pocket with the -chain showing more variability than the -chain Extensive variation makes it likely that the population will possess alleles that recognize every pathogen Extensive Diversity Makes it Extremely Unlikely that Two People are Identical at their MHC Locus If just consider HLA-A and B If 50 alleles at each locus There are 4 different molecules on the surface because of co-dominant expression Therefore odds of two people being identical is 1 in (50)4 or 1/6,250,000 Remember also HLA-C Also Class II Expression Class I there is co-dominant expression Express all three genes of both chromosomes Human Amom and Adad Bmom and B dad Cmom and Cdad Mouse Kmom and Kdad Dmom and Ddad Lmom and L dad Expression Class I there is co-dominant expression Express all three genes of both chromosomes Human Amom and Adad Bmom and B dad Cmom and Cdad Mouse Kmom and Kdad Dmom and Ddad Lmom and L dad Expression Class II also co-dominant expression on APCs Mouse IAmon and IAdad IE mon and IE dad Expression Class II also co-dominant expression on APCs Mouse IAmon and IAdad IE mon and IE dad Because Class II is made up of two chains get heterozygous complementation IAkk IAkd IAdk IAdd IEkk IEkd IEdk IEdd Never mix and chains of IA and IE Never IEIA Expression Codominant expression Heterozygote complementation Molecules with one chain from mom and one from dad For example: DP Genes expressed DP D PDP D P DP D PDP D P Proteins expressed DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP DP Never get mixed molecules between isotypes e.g. DRDQ Class 1 b MHC Molecules Limited polymorphism Class 1 b MHC Molecules CD1 Human CD1 is encoded by five nonpolymorphic and closely linked genes CD1 CD1 proteins are able to present non-peptide Ags to T cells Ags have a hydrophobic lipid tail and a hydrophilic end T cells are specific for the hydrophilic end Hydrophobic tail appears to to insert into hydrophobic pocket of CD1 Ags have a hydrophobic lipid tail and a hydrophilic end T cells are specific for the hydrophilic end Hydrophobic tail appears to to insert into hydrophobic pocket of CD1 Glucose monomycolate Free mycolate Hydrophilic Hydrophobic Phosphoinositide mannoside Natural Killer (NK) Cells- Innate Immunity Germline encoded receptors Monitor the expression of cell surface molecules that are dysregulated as a consequence of pathologic changes within cells Initiate not only NK cytotoxicity but also a general inflammatory response Natural Killer (NK) Cells- Innate Immunity Share a common early progenitor with T cells Very important against virus infection and tumors No rearrangement of receptor so develop in RAG- mice Have granules containingperforin and granzymes Natural Killer (NK) Cells- Innate Immunity Have two types of receptors: Activating receptors that initiate killing Inhibitory receptors that inhibit killing Natural Killer (NK) Cells- Innate Immunity Activating receptors that initiate killing Are associated noncovalently with other molecules containing ITAMs Natural Killer (NK) Cells- Innate Immunity Inhibitory receptors that inhibit killing Contain one or two ITIM sequences that when tyrosine phosphorylated recruit and active SHP-1 and SHP-2phosphatases Interact with class I molecules Inhibitory receptors of particular specificity expressed only by a subset of NK cells Examples: CD94/NKG2A is an inhibitory receptor. Its ligands include the nonclassical MHC-I molecules HLA-E (human) and Qa-1 (mice). These selectively bind peptides from the leader sequence of MHC-I heavy chains. NKG2D is an activating receptor. It recognizes molecules that are upregulated in stressed cells and overexpressed by epithelial tumors. The balance between inhibitory signals from receptors specific for MHC-I and stimulatory signals mediated by a variety of activating receptors ultimately determines the outcomes of an NK cell - target cell encounter The inhibitory receptor CD94/NKG2A recognizes HLA-E (human) and Qa-1 (mice). These selectively bind peptides derived from the leader sequence of MHC-1 heavy chains. Thus proper expression of HLA-E or Qa-1 is an indictor of normal expression of MHC-1 molecules. To Cell Surface 5 2-m signal peptide MHC class I ER Lumen HLA-E TAP The inhibitory receptor CD94/NKG2A recognizes HLA-E (human) and Qa-1 (mice). These selectively bind peptides derived from the leader sequence of MHC-1 heavy chains. Thus proper expression of HLA-E or Qa-1 is an indictor of normal expression of To Cell Surface MHC-1 molecules. 5 2-m signal peptide MHC class I ER Lumen HLA-E TAP HLA-E Untransfected Killing by CD94/NKG2A+NK cells + pan anti-MHC class I + anti-HLA-E + anti-CD94 + anti-HLA-C + n.a. n.a. n.a. n.a. HLA-C Transfected Transfected w ith Exogenous w ith HLA-C HLA Leader Peptide Addition + + + - + + + - + + + - To Cell Surface 5 2-m signal peptide ER Lumen HLA-E HLA-E MHC class I HLA-C TAP Untransfected Killing by CD94/NKG2A+NK cells + pan anti-MHC class I + anti-HLA-E + anti-CD94 + anti-HLA-C + n.a. n.a. n.a. n.a. Transfected Transfected w ith Exogenous w ith HLA-C HLA Leader Peptide Addition + + + - + + + - + + + - The inhibitory receptor CD94/NKG2A recognizes HLA-E. However, a cell synthesizing only HLA-E is killed because HLA-E must bind the leader sequence from a class I molecule to get to the surface. Expression of HLA-C with HLA-E provides the necessary leader sequence. Antibodies to HLA-E or to the CD94 disrupt the interactions with the inhibitory receptor and so killing takes place. Antibodies to HLA-C do not disrupt the inhibitory signal since only the leader peptide, which is acquired intracellularly, from HLA-C is required. Note that the F1 expresses the MHC proteins of both parental strains on its cells Note that the F1 expresses the MHC proteins of both parental strains on its cells For class II there will be “heterozygote complementation” Syngenic - genetically identical members of the same species Congenic - individuals that differ genetically only at a single genetic locus or region (coisogenic) Allogenic - individuals of the same species that differ genetically Multiple different inhibitory and activating receptors are being identified on NK cells. Examples are: The activating receptor NKG2D recognizes MICA and MICB, MHC-1 proteins that are upregulated in stressed cells and overexpressed by epithelial tumors. The inhibitory receptor CD94/NKG2A recognizes HLA-E (human) and Qa-1 (mice). These selectively bind peptides derived from the leader sequence of MHC-1 heavy chains. Thus proper expression of HLA-E or Qa-1 is an indictor of normal expression of MHC-1 molecules.