Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control
Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión
Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión
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Research Article AIDS/HIV Immunology

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Abstract

Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Authors

Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión

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Figure 3

Modulation of anabolic metabolism in reprogrammed CD8+ T cells.

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Modulation of anabolic metabolism in reprogrammed CD8+ T cells. (A and B...
(A and B) Total CD8+ T cells from individuals without HIV were treated with vehicle control or the GSK3 inhibitor, followed by incubation under basal conditions or with anti-CD3/anti-CD28 stimulation for 48 hours. (A) Analysis of the expression of 2-NBDG, BODIPY, MitoTracker Green, and CellROX among CD8+ T cell subsets. (B) Frequencies of 2-NBDG+, BODIPY+, MitoTracker Green+, and CellROX+ cells among CD8+ T cell subpopulations after stimulation (n = 5). (C and D) Total CD8+ T cells from individuals without HIV were treated with vehicle control or the GSK3 inhibitor, followed by incubation under basal conditions or with anti-CD3/anti-CD28 stimulation for 48 hours. (C) Flow cytometric analysis of the expression of p-S6 and p-AKT in total CD8+ T cells, and frequencies of p-S6+p-AKT+, p-S6–p-AKT+, and p-S6–p-AKT– subsets in total CD8+ T cells (n = 7). (D) Flow cytometric analysis of IL-2 and IFN-γ expression among TNF-α+CD8+ T cells, after anti-CD3/anti-CD28 stimulation. Histograms show the expression of p-S6 in the indicated cell subsets, in reprogrammed and nonreprogrammed cells. Frequency of p-S6+ cells among TNF-α+IFN-γ+IL-2+ or TNF-α+IFN-γ–IL-2– subsets (n = 6 individuals without HIV). *P < 0.05 and **P < 0.01, by Wilcoxon test (B and C) and Šidák’s multiple-comparison test (D). Data are from 2 independent experiments.