Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter

Abstract

Cytotoxic T lymphocytes recognize antigen-derived peptides bound to major histocompatibility complex (MHC) class I molecules with which they assemble in the endoplasmic reticulum or in an undefined subcompartment. There is genetic evidence that the peptides that are products of cytosolic protein degradation are transported into this compartment by a peptide supply factor (PSF), encoded in the MHC class II region. Like the corresponding genes RING4, HAM1 and mtp1, PSF is related to the multidrug-resistance family of transporters and may be a peptide pump, as translocation of peptides across membranes must occur independently of the secretory pathway. There is, however, no functional evidence for this role so far. Here we report gene transfer experiments showing that expression of PSF complementary DNA in the human lymphoblastoid cell line mutant 721.134 restores normal levels of surface HLA-A2 and -B5. No similar effect was observed in 721.174 mutant cells, in which a homozygous deletion includes PSF among several other closely linked genes. At least one of these genes may therefore also be required for PSF function.

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).…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…The classical TAP-dependent MHC-I antigen processing and presentation depends on a transporter PSF1, (TAP1 and TAP2 were primitively named as PSF1 and PSF2 respectively), to mediate entry of the cytosolic peptides into ER where they bind to class I heavy chains and promote their stable assembly with β 2 m. PSF1 is associated with a complementary transporter chain, which is polymorphic and is encoded by the PSF2 gene (3)(4)(5). Efficient antigen presentation needs intact expression of the TAP1/2 molecules.…”

TAP and TAP-like — Brothers in arms?

“…This heterodimeric transport complex consists of TAP1 (ABCB2) and TAP2 (ABCB3) (Kleijmeer et al 1992;Lacaille and Androlewicz 1998). Both subunits are essential and sufficient for antigen processing (Powis et al 1991;Spies and DeMars 1991;Meyer et al 1994). …”

“…Therefore, the formation of dimers is essential for a functional transporter. TAP1, together with TAP2, forms an active transport complex (Powis et al 1991;Spies and DeMars 1991). TAP1 or TAP2 alone are not active in peptide binding and transport .…”