Peptide-deficient forms of HLA-B: Prevalence and Function

Abstract

Abstract Human leukocyte antigen class I (HLA-I) molecules comprise a highly polymorphic heavy chain complexed to a conserved light chain, b2-microglobulin (b2m), and peptide. When bound to antigenic peptides, HLA-I molecules mediate CD8+ T cell responses against cancers and intracellular pathogens. The transporter associated with antigen processing (TAP) is the major source of cellular peptides for the assembly of HLA-I molecules in the endoplasmic reticulum (ER). Consistent with previous findings of varying stabilities of peptide-deficient forms of HLA-B, we show allotype-dependent variations in the cell surface expression of HLA-B molecules in TAP-deficient and TAP-inhibited cells. HLA-B allotypes that are resistant to inhibition of TAP (RIT-HLA-B) exist on the cell surface in empty or suboptimally loaded forms under TAP-deficiency conditions, even at physiological temperatures. Furthermore peptide-deficient forms of RIT-HLA-B allotypes bind to primary CD8+ T cells via a mode of binding that is CD8-dependent. Together, these findings indicate allotype-dependent variations in the prevalence of peptide-deficient HLA-B molecules and demonstrate previously unrecognized functions for “empty” HLA-I.