Role of Major Histocompatibility Complex in Antigen Presentation (HLA) PDF

Role of Major Histocompatibility Complex in Antigen Presentation Human Leukocyte Antigen (HLA) Nov 25, 2024 Rod Russell [email protected] Objectives The Big Picture The MHC is a cell surface protein that binds antigenic peptides and...

Role of Major Histocompatibility Complex in Antigen Presentation Human Leukocyte Antigen (HLA) Nov 25, 2024 Rod Russell [email protected] Objectives The Big Picture The MHC is a cell surface protein that binds antigenic peptides and presents them to T cells 1. Proteins are 3. The MHC:peptide degraded by the Ag- complex is then presenting cell (pAPC expressed on the cell or any cell) surface 2. The peptides 4. A T cell can only “see” associate with an Ag in a complex with MHC molecule MHC 5. Recognition of Ag:MHC will activate Jonathan W. Yewdell, Eric Reits & Jacques Neefjes the T cell Nature Reviews Immunology 3, 952-961 (December 2003)  Brief History lesson Originally discovered as the key component in transplant rejection Histocompatibility= compatible tissues MHC are a set of genes that code for MHC proteins When the MHC genes matched, transplantation worked Initial work was done in the 1930-1940’s in inbred mice strains (genetically identical) In humans, the same set of genes is called Human Leukocyte Antigen (HLA) Region of DNA in humans: HLA complex in mice: H-2 complex (historical reasons)  @ protein level: HLA = MHC @ DNA level: HLA = H-2 Organization of HLA/MHC at the DNA level 3 Classes of MHC - Class I - Class II - Class III Gene products= protein MHC on the APC presents the Ag to the TCR on the T cell APC Important: the TCR recognizes the structure that is comprised of the MHC AND the peptide. - Like a lock in a key or a neat sandwich  Structure of MHC proteins Similar to Ab’s, the interface between 2 protein domains forms the interaction region MHC Class I Molecules All MHC class I molecules are formed by an alpha (α) chain and beta2 microglobulin (β2m) The α chain is coded by either HLA-A, HLA-C or HLA-B β2m is coded by a non-MHC gene. β2m is essential for expression of all HLA class I molecules. Most polymorphic residues are located in the α1 and α2 domains that form the peptide-binding groove. MHC Class II Molecules All MHC class II molecules are formed by an alpha (α) chain and a beta (β) chain The α chain of HLA-DR molecules is non-polymorphic, the β chain is highly polymorphic (lots of different alleles) The α and β chains of HLA-DP and HLA-DQ molecules are polymorphic. Most of the polymorphic residues are in the peptide-binding groove- formed by the α1 and β1 domains.  Important: the MHC/HLA genes are variable like BCR genes are Important: don’t mix up the β’s!  Inheritance of MHC genes MHC genes are inherited as a set of MHC alleles (haplotype) from both parents, and they are inherited as a set. MHC gene products designated by numbers in humans eg. A1, B27, DR4. Example of a Haplotype m: A1; B8; DR3 Phenotype A1, 2; B8, 57; DR3, 4 p: A2; B57; DR4 MHC proteins are co-dominantly expressed (ie. ALL protein products are expressed) - Very important because it means some people have more diversity here than others based on the variation in the genes inherited - HLA genes can be associated positively or negatively with disease HLA-haplotypes transmitted as a block from parent to child Chance of 2 unrelated individuals sharing HLA identity: extremely low Chance of 2 siblings sharing HLA identity: 25% or 1/4 Both parents may have the 1 2 3 4 same allele at one locus: Child would be homozygous m: A3; B5, DR4 p: A3; B2, DR4 Child expresses 4 different HLA types HLA class I genes are expressed on all nucleated cells HLA class I and II Are Expressed on professional Antigen-Presenting Cells (pAPCs) HLA class II expression can be induced by certain cytokines Interferon-gamma (IFN-γ) (non-professional APCs deputized as APC) Important: polymorphism based on genes being expressed, but also in the combinatorial pairing in the class II genes Most of the MHC genes are highly polymorphic Exceptions: beta2 microglobulin (β2m) : none HLA-DR α : few Polygenic –many different genes are in the MHC complex Class I genes: HLA-A, HLA-C & HLA-B Class II genes: HLA-DR, HLA-DQ, & HLA-DP Polymorphic – numerous forms of the same gene in a population Allele – one of several forms of the same gene; e.g. there are hundreds of alleles of the HLA-B gene http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=genes,HL A&rid=imm.figgrp.580 Allelic variation occurs in the α1 and α2 domains of MHC-class I molecules and influences peptide binding e.g. Allele-specific pockets of HLA-A1 will differ from those of HLA-A28. Therefore each will bind different peptides and stimulate T-cells with different TCR. A single class I molecule preferentially binds peptides with certain motifs. Anchor residues in MHC I hold the peptide in place and have less variability Longer peptides can bulge out compared to shorter peptides Allelelic variation occurs in the β1 domain of most MHC-class II molecules and influences peptide binding e.g. HLA-DR4 & HLA-DR7 will bind different peptides and stimulate T-cells with different TCR. A single class II molecule preferentially binds peptides with certain motifs. Allele-specific peptide binding Clinical Relevance:  Some HLA molecules are associated with protection  Better response to a virus or a vaccine  Some HLA molecules are associated with risk  Poorer response to a virus or vaccine  Increased chance of autoimmunity Peptides that bind to Class I MHC and Class II MHC are different Proteins are processed into peptides and loaded onto MHC molecules MHC Class I - Antigen Processing and Presentation Pathway Endogenous Self-antigen antigen  Proteasome degrades proteins TAP1/2 transport peptides into the ER  MHC Class II – Exogenous Antigen Processing Pathway A. Formation of class II MHC 1. α and β chains synthesized in ER 2. Associate with invariant chain (aka Ii, CD74): acts as a chaperone (placeholder) 3. Complex enters the Golgi apparatus 4. Ii degraded to CLIP (small peptide that sits in peptide-binding groove)  MHC Class II – Exogenous Antigen Processing Pathway Exogenous antigen B. Association of exogenous peptide Only professional 1. Exogenous protein internalized APCs 2. Associates with acidic vessels containing proteases and peptidases 3. degraded into peptide fragments 4. CLIP out, peptide in: exchange catalyzed by HLA- DM 24 B cells can endocytose specific antigens after they bind to membrane bound Ab to be presented on class II MHC Recognition of the peptide:MHC by T cell starts the adaptive immune response Two Major types of T cells 1. CD4+; T helper cells - “The General” - aka bossy, older sybling 2. CD8+; Cytotoxic T cell (CTL) - “The Muscle” APC T lymphocytes (T cells) The T cell recognizes the MHC:peptide using the T cell receptor (TCR) TCR:peptide:MHC= “trimolecular complex” Cross-presentation Dendritic cells can transfer exogenous Ag to MHC class I - allows them to activate cytotoxic T cells with antigens from extracellular sources. MHC and Disease Susceptibility Some MHC alleles are associated with an increased risk for developing particular diseases or not responding to a particular vaccine For example: Individuals who have the HLA-B27 allele are 130X more likely to develop Ankylosing Spondylitis than those who do not carry the gene. Individuals who carry the HLA-DR3 and/or HLA-DR7 respond poorly to the Hepatitis Cheetahs have very limited polymorphism in B vaccine. their MHC genes & have increased susceptibility This due to the ability or inability to bind to certain viral diseases the right or wrong peptides.  Thanks! Questions???