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

Date Published: July 11, 2018

Publisher: Public Library of Science

Author(s): Jie Geng, Anita J. Zaitouna, Malini Raghavan, Nilabh Shastri.


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.

Partial Text

MHC-I molecules play a pivotal role in immune surveillance of intracellular pathogens by presenting antigenic peptides to cytotoxic T cells (CTL). They also 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]. MHC-I molecules have strong influences on disease progression in a number of infectious diseases and cancers [6, 7]. In many cases, the peptide-binding characteristics of individual MHC-I proteins are the major factor that determines immune control of diseases, but other characteristics of the MHC-I molecules, such as those relating to variations in the assembly and stability of individual MHC-I molecules, may also have an influence on disease outcomes.

Although the specific epitopes presented by HLA-I allotypes are well studied, the influences of folding and assembly variations among HLA-I allotypes on immunity are poorly characterized. Under normal conditions that are suitable for peptide loading, the effect of folding and assembly variations might not be significant. However, their effects could be amplified under pathological conditions whereby the function of PLC is disrupted by viral infection or tumorigenesis. In support of our prediction, we found that HLA-B allotypes are expressed at different levels on the surface of TAP-deficient or TAP-inhibited cells.