The T Cell Receptor and MHC Processing

MHC (Major Histocompatibility Complex) – originally defined by histocompatibility (graft rejection)

mechanism used by cells to bind immunogenic peptides and present them to the T cell receptor (TCR) at cell surface

MHC does not differentiate between "self" and "non-self" (that is the T cell’s job; no self-reactive TCRs)
bind only proteins, not T-independent antigens such as carbohydrates or nucleic acids
each MHC molecule has only one functional site and can bind only one antigenic peptide at a time

gene complex: HLA in man – contains large number of polymorphic genes

most significant: three MHC-I and three MHC-II genes – sequence motifs determined by allele
because of allelic polymorphism, most people heterozygous at all three loci, so six MHC expressed by each cell
no allelic exclusion – all MHC molecules are expressed on every cell that expresses them (codominant expr.)

nomenclature based upon historical phenotypic tissue typing, more recently by molecular cloning

human: allele specified by numerical suffix following locus designation, e.g. HLA-B27

different MHCs have different motifs

MHC I vs. MHC II

	MHC-I – infected cells; almost all cells	MHC-II – infected macrophage; APCs
Gene Loci in Man	HLA-A, HLA-B, HLA-C	HLA-DR, HLA-DP, HLA-DQ
Structure	45 kD glycosylated transmembrane chain (a 1, a 2, a 3) non-covalently associated with b 2-microglobulin (12 kD)	2 non-covalently associated, glycosylated transmembrane chains (a , 33 kD; b , 30 kD)
Peptide Binding Site	membrane-distal a 1 and a 2 domains	membrane-distal a 1 and b 1 domains
Expression	almost all cells (except RBCs), including all cells that express MHC-II	"professional antigen presenting cells" (macrophages, B cells, dendritic cells)
Regulation	Frequently constitutive	May be amplified or induced (e.g., by Ifn-g on macrophages)
Size of Peptides Bound	8-11 amino acids, usually 8-9 binding motifs at specific positions	13-17 amino acids, but variable binding motifs visible when properly aligned
Interaction with Peptides	Closed ends ("short hot dog in closed bun") limits length of peptides that can bind; free N- and C-terminal groups interact with conserved sites	Open ends ("footlong hot dog in short bun") so no size restriction; variable N- and C-terminal extensions - longer peptides are accommodated
Antigen Source	"endogenous" (from cytosol); two sources 1. protein from cytoplasmic ribosomes - viral proteins - self proteins, including tumor antigens - proteins encoded by transfected genes 2. protein that has penetrated into cytoplasm - some bacteria (e.g. Listeria, Shigella) - liposome-encapsulated vaccine antigen	"exogenous" (in vacuoles) binding enhanced at pH 5-6 (endocytic)
Antigen catabolism	Proteins cleaved to appropriate peptides by proteasome (a multisubunit multicatalytic protease complex expressed in all cells)	Lysosomal proteases; binding protects peptide from further degradation
Location of Binding	ER	endosomes, lysosomes
Peptide-MHC Binding	Antigenic peptides come to MHC-I - Peptides transported across ER membrane by TAP (Transporter for Antigen Presentation) prior to binding by MHC-I	MHC-II comes to antigenic peptides - MHC-II binds Ii ("invariant chain," a transmembrane protein) in ER, which directs transport to endocytic compartments; Ii is then proteolyzed - a small piece of Ii ("CLIP") remains in the binding site, and must be removed by HLA-DM (human; murine is H-2DM) - only then can antigenic peptide bind
Inhibitors	cycloheximide, Brefeldin A	Chloroquine
T Cell Type Bound	CD8⁺	CD4⁺

T Cell Receptors

two types of co-receptors – CD4 (binds MHC-II) and CD8 (binds MHC-I); each T-cell expresses only one ("restricted")

each binds non-polymorphic membrane proximal domains of MHC molecules; CD3 assists both in signal transduction

CD4 T cells include T helper cells (T_h) that secrete cytokines to "help" B-cell responses

CD8 T cells include CTLs (cytotoxic T lymphocytes) that lyse target cells that present specific MHC-I complexes

however, some CD4 are cytolytic, and some CD8 secrete cytokines (primarily interferon-g )