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T cell receptor and cytokine signal integration in CD8+ T cells is mediated by the protein Themis.

Joanna BrzostekNamrata GautamXiang ZhaoElijah W ChenMonika MehtaDesmond W H TungYen Leong ChuaJiawei YapSu H ChoShvetha SankaranVasily RybakinGuo FuNicholas R J Gascoigne
Published in: Nature immunology (2020)
T cell homeostasis and functional responsiveness require signals from self-peptide-major histocompatibility complex (self-pMHC) and cytokines, but the mechanisms controlling this signal integration are unknown. Using a conditional deletion of the T cell lineage-specific protein Themis, we show that Themis is required for the maintenance of peripheral CD8+ T cells and for proliferative CD8+ T cell responses to low-affinity pMHC aided by cytokines. Themis-deficient peripheral T cells show a phenotype indicative of reduced tonic signaling from self-pMHC, strongly suggesting that Themis is a positive regulator of T cell receptor signal strength in response to low-affinity self-pMHC in peripheral T cells. Signals from low-affinity pMHC and cytokines synergistically induce phosphorylation of the kinase Akt, metabolic changes and c-Myc transcription factor induction in CD8+ T cells only in the presence of Themis. This function of Themis is mediated through Shp1 phosphatase, as peripheral Themis and Shp1 double deletion rescues the peripheral CD8+ T cell maintenance.
Keyphrases
  • transcription factor
  • chemotherapy induced
  • protein kinase
  • cell proliferation
  • binding protein
  • mass spectrometry
  • small molecule
  • amino acid
  • single cell