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High-resolution repertoire analysis of Tfr and Tfh cells reveals unexpectedly high diversities indicating a bystander activation of follicular T cells

View ORCID ProfilePaul-Gydéon Ritvo, Wahiba Chaara, View ORCID ProfileKarim El Soufi, View ORCID ProfileBenjamin Bonnet, View ORCID ProfileAdrien Six, View ORCID ProfileEncarnita Mariotti-Ferrandiz, View ORCID ProfileDavid Klatzmann
doi: https://doi.org/10.1101/231977
Paul-Gydéon Ritvo
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
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Wahiba Chaara
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
2Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU-i2B), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;
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Karim El Soufi
2Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU-i2B), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;
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Benjamin Bonnet
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
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Adrien Six
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
2Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU-i2B), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;
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Encarnita Mariotti-Ferrandiz
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
2Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU-i2B), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;
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David Klatzmann
1Sorbonne Université, INSERM, UMR S 959, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France;
2Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU-i2B), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;
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  • For correspondence: david.klatzmann@upmc.fr
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ABSTRACT

T follicular helper (Tfh) and regulatory (Tfr) cells regulate B cell activation and ultimately antibody production. While concordant results show that Tfh cells are specific for the immunizing antigens, limited and even controversial results have been reported regarding the specificity of Tfr cells. Here we used high-throughput T cell receptor (TCR) sequencing to address this issue. We observed that although the Tfh- and Tfr-cell repertoires are less diverse than those of effector (Teff) and regulatory T (Treg) cells, they still represent thousands of clonotypes after immunization with a single antigen. T-cell receptor beta variable (TRBV) gene usage distinguishes both follicular T cells (Tfol) from non-Tfol cells, as well as helper (Teff and Tfh) vs. regulatory (Treg and Tfr) cells. Analysis of the sharing of clonotypes between samples revealed that a specific response to the immunizing antigen can only be detected in Tfh cells immunized with a non-self-antigen and Tfr cells immunized with a self-antigen. Finally, the Tfr TCR repertoire is more similar to that of Tregs than to that of Tfh or Teff cells. Altogether, our results highlight a bystander Tfol-cell activation during antigenic response in the germinal centres and support the Treg cell origin of Tfr cells.

Significance Statement Follicular helper T (Tfh) cells promote high-affinity antibody production by B cells while follicular regulatory T (Tfr) cells represses it. The question of the specificity of follicular T (Tfol) cells is of utmost importance in the understanding of the antibody response specificity and our work is the first to analysed the global Tfol TCR repertoire in wild type mice. This allowed us not only to portray the overall global structure of these repertoires, but also to substantiate the fact that Tfr cells respond to self-antigen while Tfh cells respond to non self-antigen, a still controversial issue. Importantly, our work revealed an unexpected bystander activation of Tfol cells. We think and discuss that it has a general significance in immune responses and possibly immunopathologies.

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Posted December 10, 2017.
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High-resolution repertoire analysis of Tfr and Tfh cells reveals unexpectedly high diversities indicating a bystander activation of follicular T cells
Paul-Gydéon Ritvo, Wahiba Chaara, Karim El Soufi, Benjamin Bonnet, Adrien Six, Encarnita Mariotti-Ferrandiz, David Klatzmann
bioRxiv 231977; doi: https://doi.org/10.1101/231977
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High-resolution repertoire analysis of Tfr and Tfh cells reveals unexpectedly high diversities indicating a bystander activation of follicular T cells
Paul-Gydéon Ritvo, Wahiba Chaara, Karim El Soufi, Benjamin Bonnet, Adrien Six, Encarnita Mariotti-Ferrandiz, David Klatzmann
bioRxiv 231977; doi: https://doi.org/10.1101/231977

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