Selected HLA-B allotypes are resistant to inhibition or deficiency of the transporter associated with antigen processing (TAP).

Jie Geng,Malini Raghavan,Anita J Zaitouna,Nilabh Shastri

doi:10.1371/journal.ppat.1007171

Abstract

Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides present in the cytosol of cells are transported into the ER via the transporter associated with antigen processing (TAP). In the ER, peptides are assembled with MHC-I molecules via the peptide-loading complex (PLC). Components of the MHC-I assembly pathway are frequently targeted by viruses, in order to evade host immunity. Many viruses encode inhibitors of TAP, which is thought to be a central source of peptides for the assembly of MHC-I molecules. However, human MHC-I (HLA-I) genes are highly polymorphic, and it is conceivable that several variants can acquire peptides via TAP-independent pathways, thereby conferring resistance to pathogen-derived inhibitors of TAP. To broadly assess TAP-independent expression within the HLA-B locus, expression levels of 27 frequent HLA-B alleles were tested in cells with deficiencies in TAP. Approximately 15% of tested HLA-B allotypes are expressed at relatively high levels on the surface of TAP1 or TAP2-deficient cells and occur in partially peptide-receptive forms and Endoglycosidase H sensitive forms on the cell surface. Synergy between high peptide loading efficiency, broad specificity for peptides prevalent within unconventional sources and high intrinsic stability of the empty form allows for deviations from the conventional HLA-I assembly pathway for some HLA-B*35, HLA-B*57 and HLA-B*15 alleles. Allotypes that display higher expression in TAP-deficient cells are more resistant to viral TAP inhibitor-induced HLA-I down-modulation, and HLA-I down-modulation-induced NK cell activation. Conversely, the same allotypes are expected to mediate stronger CD8+ T cell responses under TAP-inhibited conditions. Thus, the degree of resistance to TAP inhibition functionally separates specific HLA-B allotypes.

Highlights

Major histocompatibility complex class I (MHC-I) molecules play a pivotal role in immune surveillance of intracellular pathogens by presenting antigenic peptides to cytotoxic T cells (CTL)
We showed that cells expressing Human leukocyte antigen (HLA)-B molecules with Bw4 epitopes that are resistant to inhibition of transporter associated with antigen processing (TAP) are more resistant to the activation of KIR3DL1+ natural killer (NK) cells under TAP-inhibited conditions
Variable HLA-B cell surface expression in TAP-deficient cells In TAP-deficient cells, where the majority of peptides are prevented from entering endoplasmic reticulum (ER), most HLA-I molecules are empty or suboptimally loaded and HLA-I cell surface expression is generally significantly reduced [25,26,27]

Summary

Introduction

MHC-I molecules play a pivotal role in immune surveillance of intracellular pathogens by presenting antigenic peptides to cytotoxic T cells (CTL). They function to regulate natural killer (NK) cell activity by engaging NK cell receptors including KIR3DL1 [1], KIR2DL1/2/3 [2], CD94-NKG2A [3] and KIR3DS1 [4, 5]. ER quality control, including interactions with the PLC and calreticulin-mediated retrieval [13], contributes to the intracellular retention of empty forms of MHC-I molecules. There are known allomorph-specific differences in proteasome-dependence [24]

Methods

Results

Conclusion