Two types of human TCR differentially regulate reactivity to self and non-self antigens
Assya Trofimov,
Philippe Brouillard,
Jean-David Larouche,
Jonathan Séguin,
Jean-Philippe Laverdure,
Ann Brasey,
Gregory Ehx,
Denis-Claude Roy,
Lambert Busque,
Silvy Lachance,
Sébastien Lemieux,
Claude Perreault
Affiliations
Assya Trofimov
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
Philippe Brouillard
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
Jean-David Larouche
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
Jonathan Séguin
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Jean-Philippe Laverdure
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada; Currently Interdisciplinary Cluster for Applied Geno-Proteomics (GIGA-I3), University of Liege, Liege 4000, Belgium
Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada
Sébastien Lemieux
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; Corresponding author
Claude Perreault
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; Corresponding author
Summary: 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.
