Public T cell receptors confer high-avidity CD4 responses to HIV controllers
Daniela Benati, … , Fernando Arenzana-Seisdedos, Lisa A. Chakrabarti
Daniela Benati, … , Fernando Arenzana-Seisdedos, Lisa A. Chakrabarti
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2093-2108. https://doi.org/10.1172/JCI83792.
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Research Article AIDS/HIV

Public T cell receptors confer high-avidity CD4 responses to HIV controllers

Abstract

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.

Authors

Daniela Benati, Moran Galperin, Olivier Lambotte, Stéphanie Gras, Annick Lim, Madhura Mukhopadhyay, Alexandre Nouël, Kristy-Anne Campbell, Brigitte Lemercier, Mathieu Claireaux, Samia Hendou, Pierre Lechat, Pierre de Truchis, Faroudy Boufassa, Jamie Rossjohn, Jean-François Delfraissy, Fernando Arenzana-Seisdedos, Lisa A. Chakrabarti

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Figure 7

Public TCR transfer confers high-avidity responses and polyfunctionality to primary T cells.

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Public TCR transfer confers high-avidity responses and polyfunctionality...
(A) Cytokine production in primary CD4+ T cells mock transduced or transduced with the F24, F25, or F5 TCR and stimulated with 10–5 M Gag293. CD4+ T cells were analyzed by ICS for expression of TNF-α, MIP-1β, IL-2, IFN-γ, and CD107a. (B) ICS analysis of CD4+ T cells transduced with F24 and stimulated with decreasing Gag293 doses. Expression of the analyzed markers (% marker+) is reported as a function of peptide dose, after subtraction of background measured in unstimulated cells. (C) Summary of EC50 values measured by ICS in CD4+ T cells after TCR transduction. For each TCR, the Gag293 concentration required to achieve half-maximal expression of the 5 markers studied is reported. Mean ± SEM of EC50 values obtained for 3 independent experiments are reported. (D) Cytokine production in CD8+ T cells that were mock transduced or transduced with the F24 TCR and analyzed as in A. (E) ICS analysis of CD8+ T cells transduced with F24 and stimulated with decreasing Gag293 doses. (F) Polyfunctionality of CD4+ T cells transduced with the F24, F25, and F5 TCRs and stimulated with decreasing Gag293 doses. The number of coexpressed markers of the 5 studied (TNF-α, MIP-1β, IL-2, IFN-γ, CD107a) defines the number of functions reported in legend. Stimulation with PMA/ionomycin was used as a positive control. For A, B, D, E, and F, 1 representative experiment of 3 is shown.