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

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 TRBC1+T cells are qualitatively different from TRBC2+T 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 TRBC1+T cells than noncontrollers, raising the possibility that TRBC1+T cells might be associated with HIV control. TRBC1+T 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 %TRBC1+T 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 TRBC1+T-cell responses are of better quality than their TRBC2 counterparts, which should be considered in immunotherapeutic strategies for HIV infection. Conversely, depletion of TRBC1+T cells as part of the treatment of TRBC1+ T-cell malignancies may lead to compromised T-cell response quality.