ANTIGEN-PROCESSING AND PRESENTATION BY THE CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX

Major histocompatibility complex (MHC) class I molecules bind peptides derived from cellular proteins and display them for surveillance by t he immune system. These peptide-binding molecules are composed of a he avy chain, containing an antigen-binding groove, which is tightly asso ciated with a light chain (beta(2)-microglobulin). The majority of pre sented peptides are generated by degradation of proteins in the cytopl asm, in many cases by a large multicatalytic proteolytic particle, the proteasome. Two beta-subunits of the proteasome, LMP2 and LMP7, are i nducible by interferon-gamma and alter the catalytic activities of thi s particle, enhancing the presentation of at least some antigens. Afte r production of the peptide in the cytosol, it is transported across t he endoplasmic reticulum (ER) membrane in an ATP-dependent manner by T AP (transporter associated with antigen presentation), a member of the ATP-binding cassette family of transport proteins. There are minor pa thways for generating presented peptides directly in the ER, and some evidence suggests that peptides may be further trimmed in this locatio n. The class I heavy chain and beta(2)-microglobulin are cotranslation ally translocated into the endoplasmic reticulum where their assembly may be facilitated by the sequential association of the heavy chain wi th chaperone proteins BiP and calnexin. The class I molecule then asso ciates with the lumenal face of TAP where it is retained, presumably a waiting a peptide. After the class I molecule binds a peptide, it is r eleased for exocytosis to the cell surface where cytotoxic T lymphocyt es examine it for peptides derived from foreign proteins.