Dimorphism in the T-cell receptor constant region affects T-cell function, phenotype and HIV outcome

Abstract

OBJECTIVES: CD8 T cells recognize human leukocyte antigen-peptide complex through the T-cell receptor. Although amino acid variation in T-cell receptor variable chains often affects antigen specificity, dimorphism in the beta chain constant region (TRBC1 and TRBC2) is not thought to affect T-cell function. A recent study suggested that adoptive transfer of TRBC1-specific chimeric antigen-receptor-T cells provided an option for T-cell leukemia therapy that preserved T-cell immunity in the TRBC2 subset. This raises an important question as to whether TRBC1T cells are qualitatively different from TRBC2T cells. DESIGN: Cross-sectional study. METHODS: Sixty-six antiretroviral therapy-naive HIV-infected individuals, including 19 viraemic controllers and 47 noncontrollers, were enrolled. Peripheral blood mononuclear cells were isolated for T-cell functional assays, tetramer analyses, TRBC1 staining and immunophenotyping. RESULTS: Viraemic controllers had a higher proportion of circulating TRBC1T cells than noncontrollers, raising the possibility that TRBC1T cells might be associated with HIV control. TRBC1T cells also showed more functional T-cell responses against both HIV and cytomegalovirus (P < 0.01). The immunophenotypes of TRBC1-bearing T cells were skewed towards naive and central memory phenotypes, whereas the majority of TRBC2-expressing T cells were terminally differentiated. Inverse correlations were observed between %TRBC1T cells and HIV plasma viral load, which was most pronounced for CD8 T cells (r = -0.7096, P = 0.00002357). CONCLUSION: These data suggest that TRBC1T-cell responses are of better quality than their TRBC2 counterparts, which should be considered in immunotherapeutic strategies for HIV infection. Conversely, depletion of TRBC1T cells as part of the treatment of TRBC1 T-cell malignancies may lead to compromised T-cell response quality.