Brzostek et al. identify a critical role of Themis in CD8+ T cell homeostasis in integrating responsiveness to low-affinity self-pMHC with cytokine signaling. Themis-/- mice have fewer CD8+ T cells, which show impaired Akt pathway activation and proliferation in response to lymphopenic conditions, inflammatory cytokines, or low-affinity peptides. In an OVA- expressing bacterial infection model, transferred Themis-/- OT-1 T cells had reduced expansion and cytokine production. Double knockout of Shp1 and Themis rescued CD8+ T cell numbers, Akt activation, and cytokine responsiveness, suggesting a role of Themis in negatively regulating Shp1.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (2) Department of Microbiology and Immunolog
Author Info: (1) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (2) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (3) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (4) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (5) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (6) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (7) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (8) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (9) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (10) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (11) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. (12) State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China. (13) Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. micnrjg@nus.edu.sg. Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore. micnrjg@nus.edu.sg.
