MHC class II region encoding proteins related to the muKidrug resistance family of transmembrane transporters

Abstract

The T-cell immune response is directed against antigenic peptide fragments generated in intracellular compartments, the cytosol or the endocytic system. Peptides derived from cytosolic proteins, usually of biosynthetic origin, are presented efficiently to T-cell receptors by major histocompatibility complex (MHC) class I molecules, with which they assemble, probably in the endoplasmic reticulum (ER). In the absence of recognizable N-terminal signal sequences, such cytosolic peptides must be translocated across the ER membrane by a novel mechanism. Genes apparently involved in the normal assembly and transport of class I molecules may themselves be encoded in the MHC. Here we show that one of these, the rat cim gene, maps to a highly polymorphic part of the MHC class II region encoding two novel members of the family of transmembrane transporters related to multidrug resistance. Other members of this family of transporter proteins are known to be capable of transporting proteins and peptides across membranes independently of the classical secretory pathway. Such molecules are credible candidates for peptide pumps that move fragments of antigenic proteins from the cytosol into the ER.

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

“…These proteins are involved in the transport of molecules into the lumen of the endoplasmic reticulum and antigen presentation [67,68]. They may thus participate in the process of intracellular trafficking after cytokine exposure, a phenomenon of potential relevance for the expression of chemoattractants by beta cells in response to the pro-inflammatory stimulus [11].…”

Antigen Presentation: Discovery of the Peptide TAP

“…This month's Pillars of Immunology series features four papers published in December 1990, one in Science (1) and three in Nature (2)(3)(4), that represented a seminal advance in understanding how CTL sense virus-infected cells. CTL eliminate virus-infected cells by recognizing viral protein fragments displayed on the surface of the infected cells by MHC class I molecules.…”

“…It was known at the time that the antigenic peptides were generated in the cytosol and that these peptides joined up with MHC class I molecules in an early secretory compartment, most likely the endoplasmic reticulum (ER). 2 However, this raised the conundrum of how cytosolic peptides, most of which lacked N-terminal signal sequences, were able to cross the ER membrane. Based on the phenotype of mutant cell lines with defects in Ag presentation and the assembly of class I molecules in the ER (5-7), Alain Townsend proposed the existence of a peptide pump (8).…”

“…Jonathan Howard and Geoffrey Butcher's group had previously identified a locus in the rat MHC, termed the class I modification (cim) locus, that modified the specificity of class I-restricted Ag presentation (10). Using an overlapping set of cosmid clones covering the cim locus, they identified two expressed genes with homology to the mouse genes identified by Monaco's group (2). John Trowsdale's group came across one of the transporter genes while mining the human MHC class II locus for novel genes.…”

RFLP analysis of the MHC class III region defines unique haplotypes for the non-obese diabetic, cataract Shionogi and the non-obese non-diabetic mouse strains

“…The highly polymorphic class I and class II regions encode the receptors that bind and present processed antigens to the T cells. More recently additional genes encoding functions involved in the processing and transport of endogenous peptides, and class II-like genes have been identified [14][15][16][17]. The class III region contains the S region genes that encode components of the complement system.…”