Work

TCF-1 expression is associated with HIV-specific CD8+ T cell proliferative capacity

Year: 2017

Type: article

Abstract: Background: Many HIV cure strategies propose to elicit HIV-specific CD8+ T cell responses to control and/or eradicate the virus, but they will not be effective if they do not prevent or reverse CD8+ T cell exhaustion.A loss in proliferative capacity is a key feature of exhaustion, but little is known about how this capacity is regulated in these cells.The purpose of this study was to explore the connection between the transcription factor TCF-1 and proliferative capacity in HIV-specific CD8+ T cells.Methods: Cryopreserved PBMCs were sampled from Viremic (VL>8,000 copies/mL; n=14), ART-suppressed (VL<40 copies/mL on ART >2 years; n=10), and Controller (VL<40 copies/mL not on ART; n=12) HIV-infected individuals.Using flow cytometry, HIV-specific CD8+ T cells were identified by staining with Gag, Pol, or Nef-specific MHC Class I (HLA-A*02, *03, *24, or -B*07)-restricted tetramers.Tetramer+ cells were characterized for the expression of transcription factors (TCF-1, Tbet), effector molecules (Granzyme B), and surface proteins (PD-1, CD127, CCR7).Proliferation of the tetramer+ population was measured after 6-day in vitro peptide stimulation of CellTraceViolet (CTV)-labeled cells.Results: HIV-specific tetramer+ CD8+ T cells from Controllers versus Viremic individuals had greater proliferative responses (%CTVlo 89% vs. 16%; p=0.05), were more likely to express CD127 (26% vs. 7%; p=0.0001), and were less likely to express PD-1 (60% vs. 95%; p<0.0001).Median TCF-1 expression was highest in tetramer+ cells from Controllers, followed by ART-suppressed and Viremic individuals (62% vs. 51% vs. 35%; p<0.0001).TCF-1 expression in these cells was associated with higher CCR7 and CD127, and lower PD-1, Granzyme B, and Tbet expression.Expression of TCF-1 (but not PD-1) strongly correlated with proliferative capacity amongst Viremic and Controller individuals (r=0.83,p=0.0008), and was inversely correlated with HIV VL in Viremic individuals (r=-0.85,p=0.02).Conclusions: TCF-1 expression marks subpopulations of less terminally differentiated tetramer+ HIV-specific CD8+ T cells whose abundance correlates with enhanced proliferative capacity.Whether preservation of TCF-1+ cells is required to prevent HIV-specific T cell exhaustion remains to be investigated, but these data provide a rationale for future studies to evaluate TCF-1 as a target to enhance the efficacy of CD8+ T cell-based HIV cure strategies.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)30642-7