Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection

• Authors: Ryan J. Martinez, Emory University; Anna B. Morris, Emory University; Dennis K. Neeld, Emory University; Brian Evavold, Emory University
• Journal Title: European Journal of Immunology
• Volume: Volume 46, Number 9
• Publisher: Wiley: 12 months | 2016-09-01, Pages 2103-2110
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/eji.201646475
• Subjects: Health Sciences, Immunology; Biology, Microbiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; SHP1; T-cell homeostasis; T-cell selection; TCR signaling; Thymocyte development; REGULATORY T-CELLS; TYROSINE-PHOSPHATASE; NEGATIVE SELECTION; POSITIVE SELECTION; THEMIS; SURVIVAL; THRESHOLDS; REQUIRES; MUTANT

Abstract

SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4-Cre SHP1 fl/fl conditional knockout thymocytes using CD53, TCRβ, CD69, CD4, and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53 + ), single-positive thymocytes. Using Ca 2+ flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, postselection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT-I TCR, to reveal increased negative selection mediated by lower-affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T-cell repertoire, as its absence leads to a reduction in the numbers of CD4 + and CD8 + naïve T cells in the peripheral lymphoid compartments.