Transport Protein Genes in the Murine MHC: Possible Implications for Antigen Processing

Abstract

T lymphocyte activation requires recognition by the T cell of peptide fragments of foreign antigen bound to a self major histocompatibility complex (MHC) molecule. Genetic evidence suggests that part of the class II region of the MHC influences the expression, in trans, of MHC class I antigens on the cell surface, by regulating the availability of peptides that bind to and stabilize the class I molecule. Two closely related genes in this region, HAM1 and HAM2, were cloned and had sequence similarities to a superfamily of genes involved in the ATP-dependent transport of a variety of substrates across cell membranes. Thus, these MHC-linked transport protein genes may be involved in transporting antigen, or peptide fragments thereof, from the cytoplasm into a membrane-bounded compartment containing newly synthesized MHC molecules.

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus

“…This is surprising in view of the fact that antigen fragmentation occurs predominantly within the cytosol [35] with the low-molecular-mass polypeptide complex being part of the processing machinery [36]. Peptides thus derived are translocated into the exocytic compartment (ER, transition vesicles and Golgi apparatus) via a family of transporter proteins (TAP) [37] using signal sequences [38].…”

Cytokine regulation of expression of class I MHC antigens

“…This facilitates the production of peptides with carboxy termini suitable for binding to class I MHC groove. Transportation of peptides generated in cytoplasm, to endoplasmic reticulum is carried by TAP-1 and TAP-2 proteins present on endoplasmic reticulum membrane (Monaco et al, 1990;Spies et al, 1990;Neefjes et al, 1993;Wang et al , 1996). Both TAP-1 and TAP-2 are multimembrane spanning proteins with an AT P -binding cassette.…”

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

“…The TAP-1 and TAP-2 proteins are required for transport ofcytosolic peptides into the endoplasmatic reticulum for association with classical class I molecules (55)(56)(57). TAP-1 mutant mice are deficient in peptide transport, and consequently do not express classical class I molecules on the surface of their cells (18).…”