Two types of human TCR differentially regulate reactivity to self and non-self antigens.

[en] Based on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist throughout life, are highly shared among subjects, and are reported as disease-associated. Thus, 10%-30% of most frequent cord blood TCRs are associated with common pathogens and autoantigens. TDT-dependent TCRs present distinct structural features and are less shared among subjects. TDT-dependent TCRs are produced in maximal numbers during infancy when thymic output and TDT activity reach a summit, are more abundant in subjects with AIRE mutations, and seem to play a dominant role in graft-versus-host disease. Factors decreasing thymic output (age, male sex) negatively impact TCR diversity. Males compensate for their lower repertoire diversity via hyperexpansion of selected TCR clonotypes.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Trofimov, Assya; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Department of Computer Science and Research Operations, Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Quebec Institute for Learning Algorithms (Mila), Montreal, Quebec H2S 3H1, Canada ; Currently Fred Hutchinson Cancer Center, Seattle, WA 98109, USA ; Currently Department of Physics, University of Washington, Seattle, WA 98195-1560, USA

Brouillard, Philippe; Department of Computer Science and Research Operations, Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Quebec Institute for Learning Algorithms (Mila), Montreal, Quebec H2S 3H1, Canada

Larouche, Jean-David; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Séguin, Jonathan; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Laverdure, Jean-Philippe; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Brasey, Ann; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

Ehx, Grégory ; Université de Liège - ULiège > Département des sciences cliniques ; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Roy, Denis-Claude; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

Busque, Lambert; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

Lachance, Silvy; Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

Lemieux, Sébastien; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Department of Computer Science and Research Operations, Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Department of Biochemistry at University of Montreal, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

Perreault, Claude ; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada ; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada

Language :

English

Title :

Two types of human TCR differentially regulate reactivity to self and non-self antigens.

Publication date :

16 September 2022

Journal title :

iScience

eISSN :

2589-0042

Publisher :

Elsevier Inc., United States

Volume :

Issue :

Pages :

104968

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S2589004222012408?httpAccept=text/xml

Funders :

FRQS - Fonds de Recherche du Québec - Santé
CIHR - Canadian Institutes of Health Research

Funding text :

This study was supported by grant FDN-148400 from the Canadian Institutes of Health Research (to C.P.). A.T. was supported by a studentship from the Canadian Institutes of Health Research , and J.D.L. by a studentship from the Fonds de Recherche Québec – Santé .

Available on ORBi :

since 16 January 2023

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