Binding properties of class Ii Mhc molecules

The binding properties of class II MHC molecules can be studied using purified molecules, usually in detergent solutions, or directly in the APC. Purified class II molecules bind peptides in a homogeneous saturable process with binding affinity constants in the 10"A-10~S m range. The rate of association of peptide with the MHC molecule is slow, but once the peptide is bound it can form a very stable and long-lived complex. The complex of MHC with peptide can be assembled and isolated in free solution, and can directly trigger CD4 T cells these experiments have been done with T cell hybridomas that are triggered by the engagement of their receptor without the need of costimulatory molecules. Binding of peptides to class II MHC molecules can also be directly determined on APCs by using peptides tagged with a radioactive or fluorescent label, or with photoreactivatable probes. In live APCs the proportion of class II MHC molecules that need to be occupied by a given peptide to trigger T cells is small, usually about 0.1 % of total class II MHC (about 10-in the APCs studied so far).

The binding of peptides takes place in the antigen-binding site of the MHC molecules, which was defined through structural studies of purified complexes pioneered in the laboratory of Don Wiley and

Jack Strominger. The main architectural features are found for both the combining site of class I and II MHC molecules. For class II molecules the binding site is at the top of the molecule and consists of a groove or pocket made up of a platform of (3-pleated sheets, derived from the cij and (3, domains, surrounded by a helices, also made from portions of a, and 31 domains. Most of the amino acid residues responsible for allelic polymorphism, found in the a, and (31 domains, are located in the helices and in the platform. These residues are believed to be involved in interaction (charge or ionic, or hydrophobic) with residues in the processed protein antigen.

Peptides are found in an extended conformation with a slight twist typical of polyproline II-like conformations. Two types of interaction determine the affinity and specificity of peptide binding: those between the peptide backbone and conserved residues of the MHC molecules; and those between side-chains of critical amino acids with sites of the MHC molecule. The first set of interactions include hydrogen bonds between the conserved residues in the MHC molecules and the peptide backbone. This extensive array of hydrogen bonds contributes to the affinity of the peptide and is dependent on the length of the peptides. In contrast, side-chains of amino acids interacting with critical areas in the combining site give specificity to the interaction. The sites or areas have preference for different amino acids side-chains. The amino acid residues of the MHC pockets characterize a given MHC genotype.

Binding kinetics and competition experiments indicate the single peptide-binding site can be occupied by peptides of 8-30 amino acid residues. The specificity of peptide binding is broad, assuring that many different peptide structures can be recognized by the T cell system. Several peptide motifs that favor binding to class II MHC molecules have been identified. Not all of these motifs so far identified predict all T cell determinants. A peptide contains amino acid residues that contact the MHC binding site and other residues that contact the T cell receptor. The contact residues for MHC and T cell receptors are intermingled in the peptide. Usually 1-3 residues are solvent exposed and serve primarily to contact the T cell receptor. To note is that although there is broad binding specificity, not all peptides bind to a given allelic form of an MHC class II protein. The weak binding, or lack of it, results, as expected, in very poor activation of the specific T cells. It is the weak or poor binding of peptides to a given allelic variant of class II MHC molecules that explains many of the immune response gene effects described from early studies on inbred mice.

An important observation first made with lyso-zyme peptides is that the class II MHC binding site does not discriminate between self and nonself peptides. Self peptides have been shown to bind or not to bind, depending on their structural features. Hence, self and nonself peptides behave in the same way insofar as their binding properties to a given class II protein. Moreover, it has now been shown that APCs isolated from different tissues, including the thymus, contain self peptides associated with them. Indeed, the number of different self peptides isolated from class II molecules is in the hundreds. Some peptides derive from uptake of extracellular molecules but the majority derive from membrane proteins of the vesicular system.

The binding of self peptides to MHC molecules results in three potentially important effects: 1) on the thymus stromal cells it may be instrumental in causing the death or negative selection of maturing T cells; 2) on APCs of peripheral lymphoid tissues, self peptides may compete for the binding of foreign peptides to MHC class II molecules; and 3) such MHC-peptide complexes on APCs can potentially trigger autoreactive T cells, to cause autoimmunity. Of course, reactivity to foreign or self antigens comprises multiple steps and factors of which the generation of the MHC-peptide complex is only one.

See also: Antigen-presenting cells; Antigen presentation via MHC class I molecules; Antigens; Antigens, T dependent and independent; B lymphocyte, antigen processing and presentation; CD28; CD40 and its ligand; B7 (CD80 & C086); Dendritic cells; H2 class I; H2 class II; HLA class I; HLA class II; Invariant chain (li); MHC, functions of; MHC restriction; Phagocytosis; Second signals for lymphocyte activation.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment