Cellular & Molecular Immunology Chapter 6a

Antigen Presentation to T Lymphocytes

• Antigens entering the body are taken up by antigen presenting cells (APCs) through phagocytosis or infection.
• Some of the antigens are processed for presentation to T cells as peptides, while some are retained in their native configuration for display to B cells.
• T lymphocytes cannot interact with free antigens and can only recognize antigens displayed on APCs.

Major Histocompatibility Complex (MHC) Molecules

• MHC molecules are self-markers expressed on all host cells (except RBCs).
• MHC molecules enable T lymphocytes to recognize cell-associated antigens.
• T cell receptors (TCRs) can specifically interact with MHC-antigen complexes expressed on different cells.
• There are two types of MHC molecules: class I and class II.

Class I MHC Molecules

• Class I MHC molecules complex with intracellular/cytosolic antigens (e.g. viral peptides from virus-infected cells, antigens present in tumor cells, self and altered self peptides).
• Class I MHC molecules present peptides to CD8+ cytotoxic T cells.

Class II MHC Molecules

• Class II MHC molecules complex with extracellular/vesicular antigens (e.g. all self and non-self proteins taken up by cells via phagocytosis or endocytosis).
• Class II MHC molecules present peptides to CD4+ helper T cells.

Discovery of MHC

• The MHC was discovered as the genetic locus whose products are responsible for rapid rejection of tissue grafts exchanged between inbred strains of mice.
• MHC genes control immune responsiveness to protein antigens.
• MHC genes were initially thought to be involved only in graft rejection, but later found to be essential for immune responses to protein antigens.

Structure of MHC Molecules

• MHC molecules consist of an extracellular peptide-binding cleft (groove) followed by Ig-like domains, transmembrane, and cytoplasmic domains.
• The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft.
• The nonpolymorphic Ig-like domains of MHC molecules contain binding sites for the T cell molecules CD4 and CD8.

CD4 and CD8

• CD4 and CD8 are considered co-receptors; they do not bind to the antigen.
• CD8 interacts selectively with MHC I molecules (cytotoxic T lymphocytes).
• CD4 interacts selectively with MHC II molecules (helper T lymphocytes).

Polymorphic Residues of MHC Molecules

• MHC genes are the most polymorphic genes present in the genome of all species analyzed.
• MHC genes are always co-dominantly expressed in each individual (i.e. both classes I and II should be expressed in an individual).

Class I MHC Molecules

• Class I MHC molecules consist of 2 non-covalently linked polypeptide chains: MHC-encoded α chain and non-MHC-encoded β chain.
• The α chain possesses three main moieties: extracellular region, transmembrane region, and cytoplasmic region.

Class II MHC Molecules

• Class II MHC molecules consist of 2 non-covalently linked polypeptide chains: α chain and β chain.
• The α and β chains of MHC II molecules possess three main moieties: extracellular region, transmembrane region, and cytoplasmic region.

Peptide Binding to MHC Molecules

• For a protein to be immunogenic in an individual, processing by an APC must produce peptides that can bind to the MHC molecules of that individual.
• Each MHC I and MHC II molecule has a single peptide-binding cleft (but it can bind many, different peptides).
• The binding of peptides to MHC molecules is a non-covalent interaction mediated by residues both in the peptides and in the peptide-binding clefts of MHC molecules.

Genomic Organization of MHC Molecules

• Many of the proteins involved in the processing of antigenic peptides and presentation of such peptides to T cells are encoded by genes located within the MHC genes.
• Within class II and I loci are genes that encode several proteins that play critical roles in antigen processing.

Expression of MHC Molecules

• Class I molecules are constitutively expressed on virtually all nucleated cells.
• Class II molecules are normally expressed on APCs (dendritic cells, B cells, macrophages) and a few other cell types following induction.
• The expression of MHC molecules is modulated by cytokines produced during both innate and adaptive immune responses.