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

Daniela Benati, Moran Galperin, Olivier Lambotte, Stephanie Gras, Annick Lim, Madhura Mukhopadhyay, Alexandre Nouel, Kristy-Anne Campbell, Brigitte Lemercier, Mathieu Claireaux, Samia Hendou, Pierre Lechat, Pierre De Truchis, Faroudy Boufassa, Jamie Rossjohn, Jean-Francois Delfraissy, Fernando Arenzana-Seisdedos, Lisa Chakrabarti

Research output: Contribution to journal › Article › Research › peer-review

19 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2093-2108
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

Cite this

Benati, D., Galperin, M., Lambotte, O., Gras, S., Lim, A., Mukhopadhyay, M., ... Chakrabarti, L. (2016). Public T cell receptors confer high-avidity CD4 responses to HIV controllers. Journal of Clinical Investigation, 126(6), 2093-2108. https://doi.org/10.1172/JCI83792
Benati, Daniela ; Galperin, Moran ; Lambotte, Olivier ; Gras, Stephanie ; Lim, Annick ; Mukhopadhyay, Madhura ; Nouel, Alexandre ; Campbell, Kristy-Anne ; Lemercier, Brigitte ; Claireaux, Mathieu ; Hendou, Samia ; Lechat, Pierre ; De Truchis, Pierre ; Boufassa, Faroudy ; Rossjohn, Jamie ; Delfraissy, Jean-Francois ; Arenzana-Seisdedos, Fernando ; Chakrabarti, Lisa. / Public T cell receptors confer high-avidity CD4 responses to HIV controllers. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 6. pp. 2093-2108.
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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.",
author = "Daniela Benati and Moran Galperin and Olivier Lambotte and Stephanie Gras and Annick Lim and Madhura Mukhopadhyay and Alexandre Nouel and Kristy-Anne Campbell and Brigitte Lemercier and Mathieu Claireaux and Samia Hendou and Pierre Lechat and {De Truchis}, Pierre and Faroudy Boufassa and Jamie Rossjohn and Jean-Francois Delfraissy and Fernando Arenzana-Seisdedos and Lisa Chakrabarti",
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Benati, D, Galperin, M, Lambotte, O, Gras, S, Lim, A, Mukhopadhyay, M, Nouel, A, Campbell, K-A, Lemercier, B, Claireaux, M, Hendou, S, Lechat, P, De Truchis, P, Boufassa, F, Rossjohn, J, Delfraissy, J-F, Arenzana-Seisdedos, F & Chakrabarti, L 2016, 'Public T cell receptors confer high-avidity CD4 responses to HIV controllers', Journal of Clinical Investigation, vol. 126, no. 6, pp. 2093-2108. https://doi.org/10.1172/JCI83792

Public T cell receptors confer high-avidity CD4 responses to HIV controllers. / Benati, Daniela; Galperin, Moran; Lambotte, Olivier; Gras, Stephanie; Lim, Annick; Mukhopadhyay, Madhura; Nouel, Alexandre; Campbell, Kristy-Anne; Lemercier, Brigitte; Claireaux, Mathieu; Hendou, Samia; Lechat, Pierre; De Truchis, Pierre; Boufassa, Faroudy; Rossjohn, Jamie; Delfraissy, Jean-Francois; Arenzana-Seisdedos, Fernando; Chakrabarti, Lisa.

In: Journal of Clinical Investigation, Vol. 126, No. 6, 01.06.2016, p. 2093-2108.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Public T cell receptors confer high-avidity CD4 responses to HIV controllers

AU - Benati, Daniela

AU - Galperin, Moran

AU - Lambotte, Olivier

AU - Gras, Stephanie

AU - Lim, Annick

AU - Mukhopadhyay, Madhura

AU - Nouel, Alexandre

AU - Campbell, Kristy-Anne

AU - Lemercier, Brigitte

AU - Claireaux, Mathieu

AU - Hendou, Samia

AU - Lechat, Pierre

AU - De Truchis, Pierre

AU - Boufassa, Faroudy

AU - Rossjohn, Jamie

AU - Delfraissy, Jean-Francois

AU - Arenzana-Seisdedos, Fernando

AU - Chakrabarti, Lisa

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/27111229

U2 - 10.1172/JCI83792

DO - 10.1172/JCI83792

M3 - Article

VL - 126

SP - 2093

EP - 2108

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -

Benati D, Galperin M, Lambotte O, Gras S, Lim A, Mukhopadhyay M et al. Public T cell receptors confer high-avidity CD4 responses to HIV controllers. Journal of Clinical Investigation. 2016 Jun 1;126(6):2093-2108. https://doi.org/10.1172/JCI83792

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