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

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

Nat Immunol. 2023 Dec;24(12):2121-2134. doi: 10.1038/s41590-023-01663-2. Epub 2023 Nov 9.

Authors

Guillaume Gaud¹, Sooraj Achar^#^{2

3}, François X P Bourassa^#^{4

5}, John Davies^#^{6

7}, Teri Hatzihristidis¹, Seeyoung Choi¹, Taisuke Kondo⁸, Selamawit Gossa⁹, Jan Lee¹, Paul Juneau¹⁰, Naomi Taylor⁸, Christian S Hinrichs^{6

11}, Dorian B McGavern⁹, Paul François^{4

12}, Grégoire Altan-Bonnet², Paul E Love¹³

Affiliations

¹ Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA.
² Immunodynamics Section, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
³ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
⁴ Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, Quebec, Canada.
⁵ Department of Physics, McGill University, Montréal QC, Canada.
⁶ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁷ Department of Safety Assessment, Genentech, Inc., San Francisco, CA, USA.
⁸ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁹ Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
¹⁰ National Institutes of Health Library, Office of Research Services, National Institutes of Health, Bethesda, MD, USA.
¹¹ Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹² Mila Québec, Montréal, Quebec, Canada.
¹³ Hematopoiesis and Lymphocyte Biology Section, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Bethesda, MD, USA. [email protected].

^# Contributed equally.

Abstract

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.

MeSH terms

Animals
CD3 Complex
Immunoreceptor Tyrosine-Based Activation Motif*
Ligands
Mice
Peptides
Receptors, Antigen, T-Cell*
T-Lymphocytes

Substances

CD3 Complex
Ligands
Peptides
Receptors, Antigen, T-Cell
CD3 antigen, zeta chain

Abstract

MeSH terms

Substances

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