title: T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response.
abstract: Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response.
authors.affiliation: Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Eugenio A
authors.initials: EA
authors.lastname: Carrera Silva
authors.forename: Pamela Y
authors.initials: PY
authors.lastname: Chan
authors.forename: Leonel
authors.initials: L
authors.lastname: Joannas
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Errasti
authors.forename: Nicola
authors.initials: N
authors.lastname: Gagliani
authors.forename: Lidia
authors.initials: L
authors.lastname: Bosurgi
authors.forename: Maurice
authors.initials: M
authors.lastname: Jabbour
authors.forename: Anthony
authors.initials: A
authors.lastname: Perry
authors.forename: Faye
authors.initials: F
authors.lastname: Smith-Chakmakova
authors.forename: Daniel
authors.initials: D
authors.lastname: Mucida
authors.forename: Hilde
authors.initials: H
authors.lastname: Cheroutre
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Leighton
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Carla V
authors.initials: CV
authors.lastname: Rothlin
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017293:Protein S / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D017293:Protein S; D020794:Receptor Protein-Tyrosine Kinases