Abstract
Original language | English |
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Pages (from-to) | 2093-2108 |
Number of pages | 16 |
Journal | Journal of Clinical Investigation |
Volume | 126 |
Issue number | 6 |
DOIs | |
Publication status | Published - 1 Jun 2016 |
Cite this
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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 -