Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells.
Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis.
Ludwig Centre for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Swiss Vaccine Research Institute, Lausanne University Hospital, 1066 Epalinges, Switzerland; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1066 Epalinges, Switzerland; hughrobson.macdonald@unil.ch vijaykumar.chennupati@unil.ch.
Vijaykumar
V
Chennupati
Swiss Federal Institute of Technology Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland;
Ute
0000-0001-7914-7061
U
Koch
Department of Biochemistry, World Health Organization Immunology Research and Training Centre, University of Lausanne, 1066 Epalinges, Switzerland; and.
Manuel
M
Coutaz
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Leonardo
L
Scarpellino
Department of Biochemistry, World Health Organization Immunology Research and Training Centre, University of Lausanne, 1066 Epalinges, Switzerland; and.
Fabienne
F
Tacchini-Cottier
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Sanjiv A
SA
Luther
Swiss Federal Institute of Technology Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland;
Freddy
F
Radtke
Swiss Vaccine Research Institute, Lausanne University Hospital, 1066 Epalinges, Switzerland; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1066 Epalinges, Switzerland;
Dietmar
D
Zehn
Ludwig Centre for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; hughrobson.macdonald@unil.ch vijaykumar.chennupati@unil.ch.
H Robson
HR
MacDonald
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D051880:Receptors, Notch