The checkpoint for agonist selection precedes conventional selection in human thymus

Greet Verstichel; David Vermijlen; Liesbet Martens; Glenn Goetgeluk; Margreet Brouwer; Nicolas Thiault; Yasmine Van Caeneghem; Stijn De Munter; Karin Weening; Sarah Bonte; Georges Leclercq; Tom Taghon; Tessa Kerre; Yvan Saeys; Jo Van Dorpe; Hilde Cheroutre; Bart Vandekerckhove

doi:10.1126/sciimmunol.aah4232

The checkpoint for agonist selection precedes conventional selection in human thymus

Sci Immunol. 2017 Feb 24;2(8):eaah4232. doi: 10.1126/sciimmunol.aah4232.

Authors

Greet Verstichel¹, David Vermijlen^{2

3}, Liesbet Martens⁴, Glenn Goetgeluk¹, Margreet Brouwer³, Nicolas Thiault⁵, Yasmine Van Caeneghem¹, Stijn De Munter¹, Karin Weening¹, Sarah Bonte¹, Georges Leclercq¹, Tom Taghon¹, Tessa Kerre¹, Yvan Saeys^{4

6}, Jo Van Dorpe⁷, Hilde Cheroutre⁵, Bart Vandekerckhove⁸

Affiliations

¹ Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, MRB2, De Pintelaan 185, 9000 Ghent, Belgium.
² Department of Biopharmacy, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, accès 2, 1050 Brussels, Belgium.
³ Institute for Medical Immunology, ULB, Rue Adrienne Bolland 8, 6041 Gosselies, Belgium.
⁴ Data Mining and Modeling for Systems Immunology, Vlaams Instituut voor Biotechnologie Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
⁵ Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
⁶ Department of Internal Medicine, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁷ Faculty of Medicine and Health Sciences, Department of Medical and Forensic Pathology, Ghent University, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.
⁸ Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, MRB2, De Pintelaan 185, 9000 Ghent, Belgium. bart.vandekerckhove@ugent.be.

Abstract

The thymus plays a central role in self-tolerance, partly by eliminating precursors with a T cell receptor (TCR) that binds strongly to self-antigens. However, the generation of self-agonist-selected lineages also relies on strong TCR signaling. How thymocytes discriminate between these opposite outcomes remains elusive. Here, we identified a human agonist-selected PD-1⁺ CD8αα⁺ subset of mature CD8αβ⁺ T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post-β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAV) and T cell receptor alpha joining (TRAJ) rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in the human thymus.

Abstract

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