Abstract
The highly polymorphic human leukocyte antigen (HLA) class I molecules present peptide antigens to CD8+ T cells, inducing immunity against infections and cancers. Quality control mediated by peptide loading complex (PLC) components is expected to ensure the cell surface expression of stable peptide-HLA class I complexes. This is exemplified by HLA-B*08:01 in primary human lymphocytes, with both expression level and half-life at the high end of the measured HLA-B expression and stability hierarchies. Conversely, low expression on lymphocytes is measured for three HLA-B allotypes that bind peptides with proline at position 2, which are disfavored by the transporter associated with antigen processing. Surprisingly, these lymphocyte-specific expression and stability differences become reversed or altered in monocytes, which display larger intracellular pools of HLA class I than lymphocytes. Together, the findings indicate that allele and cell-dependent variations in antigen acquisition pathways influence HLA-B surface expression levels, half-lives and receptivity to exogenous antigens.
Highlights
Major histocompatibility complex (MHC) class I proteins are cell surface proteins that control immune responses by CD8+ T cells and natural killer (NK) cells
Important points to consider in assessing allelic variations in human leukocyte antigen (HLA) class I cell surface expression are (a) the specificities of antibodies used for the expression assessments and (b) potential differences in the binding affinities of detecting antibodies towards the HLA class I allotypes that are being compared
HLA-B alleles do not vary in their mRNA expression in individual lymphocyte subsets, as previously described in bulk Peripheral blood mononuclear cells (PBMCs) (Figure 1—figure supplements 4 and 5 and (Ramsuran et al, 2017)
Summary
Major histocompatibility complex (MHC) class I proteins are cell surface proteins that control immune responses by CD8+ T cells and natural killer (NK) cells. We addressed the hypothesis that peptide pool limitations induced by mismatched peptide-binding preferences between TAP and HLA class I allotypes affects cell surface expression levels of HLA class I molecules, via suboptimal assembly. To address this hypothesis, we used freshly-isolated human lymphocytes and monocytes and quantitative flow cytometry to examine the expression levels of HLA-B alleles in an Ann Arbor, United States cohort of healthy donors. We compared exogenous peptide receptivity of HLA-B allotypes with high or low cell surface stability to assess variations
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