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
View: Text | PDF | Corrigendum
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

×

Figure 1

Induction of stem-like CD8+ T cells with high survival capacity and polyfunctionality by in vitro reprogramming.

Options: View larger image (or click on image) Download as PowerPoint
Induction of stem-like CD8+ T cells with high survival capacity and poly...
Total CD8+ T cells from individuals without HIV were treated with medium, vehicle (Veh.) control, or the GSK3 inhibitor (inh), followed by incubation under basal conditions or with anti-CD3/anti-CD28 stimulation for 48 hours. (A and B) Analysis of CD8+ T cell subpopulations in unstimulated cells (n = 4). (C) Fold change of CD8+ T cell subpopulations upon vehicle control or GSK3 inhibitor treatment, relative to the medium alone condition (n = 4). (D) Expression of TCF-1 in CD8+ T cell subsets (n = 4). (E) Fold change in the expression of the indicated markers induced by anti-CD3/anti-CD28 antibody stimulation relative to unstimulated cells (n = 5). (F) Analysis of dead cells by Aqua LIVE/DEAD+ staining (Aqua L/D) among total and T-bet+CD8+ T cells, and fold change in dead CD8+ T cells induced by anti-CD3/anti-CD28 stimulation relative to the unstimulated (Unstim.) condition (n = 5). (G) Frequencies of granzyme B+ (GZMB+), IL-2+, IFN-γ+, and TNF-α+ CD8+ T cells after anti-CD3/anti-CD28 stimulation. (H) Expression of 1 to 4 functions in CD8+ T cells (n = 5). *P < 0.05, by Dunn’s test (B) and Wilcoxon test (C, D, and F–H). Data obtained from 2 (A–F) or 3 (G and H) independent experiments are shown.