CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides

Guillaume Gaud; Sooraj Achar; François X P Bourassa; John Davies; Teri Hatzihristidis; Seeyoung Choi; Taisuke Kondo; Selamawit Gossa; Jan Lee; Paul Juneau; Naomi Taylor; Christian S Hinrichs; Dorian B McGavern; Paul François; Grégoire Altan-Bonnet; Paul E Love

doi:10.1038/s41590-023-01663-2

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CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides

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CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides

Guillaume Gaud, Sooraj Achar, François X P Bourassa, John Davies, Teri Hatzihristidis, Seeyoung Choi, Taisuke Kondo, Selamawit Gossa, Jan Lee, Paul Juneau, …

Nature immunology, Vol.24(12), pp.2121-2134

12/2023

DOI: https://doi.org/10.1038/s41590-023-01663-2

PMID: 37945821

Résumé

Animals

CD3 Complex

Immunoreceptor Tyrosine-Based Activation Motif

Ligands

Mice

Peptides

Receptors, Antigen, T-Cell

T-Lymphocytes

The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we evaluated the effect of inactivating the three CD3ζ chain ITAMs on TCR signaling and T cell effector responses using a conditional 'switch' mouse model. Unexpectedly, we found that T cells expressing TCRs containing inactivated (non-signaling) CD3ζ ITAMs (6F-CD3ζ) exhibited reduced ability to discriminate between low- and high-affinity ligands, resulting in enhanced signaling and cytokine responses to low-affinity ligands because of a previously undetected inhibitory function of CD3ζ ITAMs. Also, 6F-CD3ζ TCRs were refractory to antagonism, as predicted by a new in silico adaptive kinetic proofreading model that revises the role of ITAM multiplicity in TCR signaling. Finally, T cells expressing 6F-CD3ζ displayed enhanced cytolytic activity against solid tumors expressing low-affinity ligands, identifying a new counterintuitive approach to TCR-mediated cancer immunotherapy.

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Détails

Titre: CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides
Créateurs - sans rôle: Guillaume Gaud - Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA
Sooraj Achar - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
François X P Bourassa - Department of Physics, McGill University, Montréal QC, Canada
John Davies - Department of Safety Assessment, Genentech, Inc., San Francisco, CA, USA
Teri Hatzihristidis - Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA
Seeyoung Choi - Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA
Taisuke Kondo - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Selamawit Gossa - Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Jan Lee - Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA
Paul Juneau - National Institutes of Health Library, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
Naomi Taylor - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Christian S Hinrichs - Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
Dorian B McGavern - Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Paul François - Mila Québec, Montréal, Quebec, Canada
Grégoire Altan-Bonnet - Immunodynamics Section, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Paul E Love - Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA. lovep@mail.nih.gov
Détails de publication: Nature immunology, Vol.24(12), pp.2121-2134
Note de subvention: ZIA NS003111 / Intramural NIH HHS HD001803-28 / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ZIA HD001803 / Intramural NIH HHS
Identifiants: 99139791009311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article