T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response

Eugenio A. CarreraSilva, Pamela Y. Chan, Leonel Joannas, Andrea E. Errasti, Nicola Gagliani, Lidia Bosurgi, Maurice Jabbour, Anthony Perry, Faye Smith-Chakmakova, Daniel Mucida, Hilde Cheroutre, Tal Burstyn-Cohen, Jonathan A. Leighton, Greg Lemke, Sourav Ghosh*, Carla V. Rothlin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

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 overreactiveimmune responses. Tcells, 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 Tcells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to Tcell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human Tcells, 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.

Original languageAmerican English
Pages (from-to)160-170
Number of pages11
JournalImmunity
Volume39
Issue number1
DOIs
StatePublished - 25 Jul 2013

Bibliographical note

Funding Information:
We thank R. Medzhitov for critical reading of this manuscript. We also thank S. Huber, A. Iwasaki, P. Kavathas, P. Lincona-Limón, S. Nish, D. Schenten and E. Zuniga for helpful suggestions and discussions. This research was supported by grants from the National Institutes of Health (R01 AI077058 to G.L., R01 AI089824 to C.V.R. and S.G., CA95060 to S.G., and T32 AI007019 to P.Y.C), by the Crohn’s and Colitis Foundation (to C.V.R and S.G.), by the American Heart Association (C.V.R), American Asthma Foundation (C.V.R.), Lupus Research Institute (C.V.R), CONICET Postdoctoral Fellowship (A.E.E.), and a Gershon-Trudeau Postdoctoral Fellowship (E.A.C.S.).

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