SLAM receptors foster iNKT cell development by reducing TCR signal strength after positive selection

Yan Lu; Ming-Chao Zhong; Jin Qian; Virginie Calderon; Mayra Cruz Tleugabulova; Thierry Mallevaey; André Veillette

doi:10.1038/s41590-019-0334-0

SLAM receptors foster iNKT cell development by reducing TCR signal strength after positive selection

Nat Immunol. 2019 Apr;20(4):447-457. doi: 10.1038/s41590-019-0334-0. Epub 2019 Mar 4.

Authors

Yan Lu¹, Ming-Chao Zhong¹, Jin Qian¹, Virginie Calderon², Mayra Cruz Tleugabulova³, Thierry Mallevaey^{3

4}, André Veillette^{5

6

7}

Affiliations

¹ Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
² Bioinformatics Core Facility, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
³ Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
⁴ Institute of Biomaterials & Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁵ Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada. [email protected].
⁶ Department of Medicine, University of Montréal, Montréal, Québec, Canada. [email protected].
⁷ Department of Medicine, McGill University, Montréal, Québec, Canada. [email protected].

PMID: 30833791
DOI: 10.1038/s41590-019-0334-0

Abstract

Invariant natural killer T cells (iNKT cells) develop through an incompletely understood process that requires positive selection by CD4⁺CD8⁺ double-positive thymocytes and SLAM family receptors (SFRs). Here we found that SFRs promoted the development of iNKT cells by reducing the strength of the T cell antigen receptor (TCR) signal after positive selection. This effect improved the survival of iNKT cells and their responses to antigen. Loss of SFRs upregulated the expression of inhibitory receptors, including PD-1, on iNKT cells to mitigate the deleterious effect of SFR deficiency. The role of SFRs could be mimicked by expression of SLAMF6 alone in SFR-deficient mice, and this involved the adaptor SAP-kinase Fyn complex and the phosphatase SHP-1. Thus, SFRs foster iNKT cell development by attenuating TCR signal strength after positive selection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cell Survival
Costimulatory and Inhibitory T-Cell Receptors / metabolism
Humans
Mice
Mice, Knockout
Natural Killer T-Cells / enzymology
Natural Killer T-Cells / immunology*
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Proto-Oncogene Proteins c-fyn / metabolism
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism*
Signal Transduction
Signaling Lymphocytic Activation Molecule Associated Protein / genetics
Signaling Lymphocytic Activation Molecule Family / genetics
Signaling Lymphocytic Activation Molecule Family / metabolism
Signaling Lymphocytic Activation Molecule Family / physiology*

Substances

Costimulatory and Inhibitory T-Cell Receptors
Proto-Oncogene Proteins c-bcl-2
Receptors, Antigen, T-Cell
SLAMF6 protein, human
Sh2d1a protein, mouse
Signaling Lymphocytic Activation Molecule Associated Protein
Signaling Lymphocytic Activation Molecule Family
Slamf6 protein, mouse
Proto-Oncogene Proteins c-fyn
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Ptpn6 protein, mouse