α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

Abstract

Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4. HLA-A11svE4 is located on the cell surface without b2-microglobulin (b2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with b2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with b2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8 + T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

Alternative splicing of MR1 regulates antigen presentation to MAIT cells

“…Overlay histograms of MR1AGFP expression following MR1B (third) transfection as described in Fig. 6B with gMFI www.nature.com/scientificreports/ cytotoxicity of the HIV-infected cell 41 . Alternative splicing of the non-classical molecule HLA-G has been reported and is hypothesized to be associated with protection of the developing fetus 42,43 .…”

“…However, the role of alternative splicing in the regulation of MHC and subsequent acquisition of adaptive immunity is incompletely explored. An α3 domain deletion mutant of HLA-A11 can promote evasion of NK cell mediated cytotoxicity of the HIV-infected cell 41 . Alternative splicing of the non-classical molecule HLA-G has been reported and is hypothesized to be associated with protection of the developing fetus 42 , 43 .…”

Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions

“…Increasing HLA-1-exon4 skipping Inhibiting the activation of natural killer cells [78] RUNX1 RUNX1a, RUNX1b, and RUNX1c…”