Major Histocompatibility Complex in Immunology

Major Histocompatibility Complex (MHC) in Antigen Presentation

• MHC genes code for Human Leukocyte Antigens (HLA)
• HLA class I and class II genes differ structurally and functionally
• HLA class I and class II molecules process and present antigens differently
• HLA class I and II genes are expressed on different cell types
• HLA polymorphism influences disease susceptibility and transplant rejection
• MHC proteins are co-dominantly expressed

The MHC as a Cell Surface Protein

• MHC is a cell surface protein binding antigenic peptides
• MHC proteins present peptides to T cells
• Proteins are degraded by the Antigen-Presenting Cell (APC) or any cell
• Peptides associate with MHC molecules
• MHC-peptide complex is expressed on the cell surface
• A T cell identifies an antigen complexed with MHC
• Recognition of antigen:MHC activates the T cell

The Big Picture of Immune Response

• Primary immune response involves NK cells, CD4+ T cells, CD8+ T cells, B cells
• Memory B and plasma cells, and Memory CD4 and CD8 T cells are created

Brief History of MHC

• MHC was initially discovered as a crucial component in transplant rejection
• Histocompatibility refers to tissues being compatible
• MHC genes were studied in genetically identical mice
• In humans, the same set of genes is known as Human Leukocyte Antigen (HLA)
• The mice equivalent is the H-2 complex

Organization of HLA/MHC

•  HLA/MHC are organized in 3 classes
• Proteins are generated from genes in the MHC complex
• HLA class I consists of α chains and β2 microglobulin (ẞ2m)
• HLA class II comprises an α chain and a β chain
• Different HLA haplotypes can be present (gene variants)
• HLA-DP, HLA-DQ, and HLA-DR are MHC class II genes
• Most polymorphic residues are found within the peptide-binding groove

MHC on APC and TCR

• MHC molecule on Antigen Presenting Cell (APC) presents antigen to T cell receptor
• T cell receptors (TCRs) recognize the MHC-peptide complex
• This interaction structure is comparable to a lock and key

Structure of MHC Proteins

• MHC proteins are transmembrane proteins
•  The structure resembles immunoglobulins (Abs)

MHC Class I Molecules

• MHC class I molecules are formed by an alpha chain and beta-2 microglobulin
• HLA-A, HLA-B, and HLA-C alleles encode alpha chains
• 2 m is essential for HLA class I expression

MHC Class II Molecules

• HLA-DP, HLA-DQ, and HLA-DR alleles encode class II molecules
• HLA-DR alpha and beta chains are polymorphic

Proteins and Peptides in MHC

• Proteins that are degraded into peptides are loaded onto MHC molecules
• Proteasome processes endogenous proteins into peptides
• TAP1/2 is responsible for peptide transportation into endoplasmic reticulum (ER)

MHC Class II - Exogenous Antibody Pathway

• Class II MHC formation: α and β chains are synthesized and combined with invariant chain (Ii) in the endoplasmic reticulum
• Invariant chain to a placeholder that is degraded into CLIP (small peptide)
• Peptides are produced from the exogenous antigen that is taken up by the APC, then degraded in acidic vesicles
• CLIP exchange: MHC-peptide complex is formed by replacing CLIP with a peptide, mediated by HLA DM
• Peptides bind to MHC molecules in MHC-peptide complex form

MHC Antigen Binding - Binding Differences

• The peptides that bind to class I MHC are different from those that bind to class II MHC

Cross-Presentation

• Dendritic cells transfer exogenous antigens to MHC class I molecules
• This allows them to activate cytotoxic T cells using antigens from outside the cell

MHC and Diseases

• Some HLA alleles are linked to increased risks for certain diseases
• HLA variation results in differing responses to vaccines

Recognition of Peptide:MHC by T Cell

• Recognition of peptide bound to MHC by T cells initiates the adaptive immune response
• Two main types of T cells: CD4+ T-helper and CD8+ cytotoxic T cells
• The T cell receptor (TCR) interacts with the Peptide:MHC to drive an adaptive immune response