THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1

Seeyoung Choi; Claude Warzecha; Ekaterina Zvezdova; Jan Lee; Jérémy Argenty; Renaud Lesourne; L Aravind; Paul E Love

doi:10.1038/ni.3692

THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1

Nat Immunol. 2017 Apr;18(4):433-441. doi: 10.1038/ni.3692. Epub 2017 Feb 27.

Authors

Seeyoung Choi¹, Claude Warzecha¹, Ekaterina Zvezdova¹, Jan Lee¹, Jérémy Argenty^{2

3}, Renaud Lesourne^{2

3}, L Aravind⁴, Paul E Love¹

Affiliations

¹ Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
² Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
³ Institut National de la Santé et de la Recherche Médicale, U1043, Centre National de la Recherche Scientifique, U5282, and Université de Toulouse, Université Paul Sabatier, Toulouse, France.
⁴ National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 28250424
PMCID: PMC5807080
DOI: 10.1038/ni.3692

Abstract

THEMIS, a T cell-specific protein with high expression in CD4⁺CD8⁺ thymocytes, has a crucial role in positive selection and T cell development. THEMIS lacks defined catalytic domains but contains two tandem repeats of a distinctive module of unknown function (CABIT). Here we found that THEMIS directly regulated the catalytic activity of the tyrosine phosphatase SHP-1. This action was mediated by the CABIT modules, which bound to the phosphatase domain of SHP-1 and promoted or stabilized oxidation of SHP-1's catalytic cysteine residue, which inhibited the tyrosine-phosphatase activity of SHP-1. Deletion of SHP-1 alleviated the developmental block in Themis^-/- thymocytes. Thus, THEMIS facilitates thymocyte positive selection by enhancing the T cell antigen receptor signaling response to low-affinity ligands.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Cell Differentiation / genetics
Cell Differentiation / immunology
Cell Line
Clonal Selection, Antigen-Mediated / immunology*
Gene Deletion
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Mice, Knockout
Oxidation-Reduction
Protein Binding
Protein Interaction Domains and Motifs
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
Reactive Oxygen Species / metabolism
Receptors, Antigen, T-Cell / metabolism*
Signal Transduction*
T-Lymphocytes / cytology
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism*
Thymocytes / cytology
Thymocytes / immunology
Thymocytes / metabolism

Substances

Intracellular Signaling Peptides and Proteins
Reactive Oxygen Species
Receptors, Antigen, T-Cell
thymocyte-expressed molecule involved in selection, human
Protein Tyrosine Phosphatase, Non-Receptor Type 6

Abstract

Publication types

MeSH terms

Substances

Grants and funding