Journal Article

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

Gascoigne, Nicholas R. J., Brzostek, Joanna, Tung, Desmond W. H., Gautam, Namrata, Yap, Jiawei, Fu, Guo, Mehta, Monika, Chua, Yen Leong, Sankaran, Shvetha, Rybakin, Vasily, Chen, Elijah W., Zhao, Xiang, Cho, Su H.

2020

Overview

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. T cell homeostasis requires integration of signals from antigen and cytokine receptors. Gascoigne and colleagues demonstrate that the protein Themis supports signals from low-affinity TCR ligands to maintain normal CD8 + cell function.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250 / 631/80 / Affinity / AKT protein / Animals / Biomedical and Life Sciences / Biomedicine / c-Myc protein / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell lineage / Clonal deletion / Cytokine receptors / Cytokines / Cytokines - immunology / Histocompatibility / Homeostasis / Immunology / Infectious Diseases / Integration / Intercellular Signaling Peptides and Proteins - immunology / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Mice / Mice, Knockout / Myc protein / Phenotypes / Phosphorylation / Proteins / Receptors, Antigen, T-Cell, alpha-beta - immunology / SHP-1 protein / Signal Transduction - immunology / T cell receptors