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Neurokinin 1 receptor-signaling sustains T-cell survival during thymus development and following T-cell activation in secondary lymphoid organs

Authors :
Adriana T. Larregina
Tina L. Sumpter
Darling M. Rojas-Canales
Olga A. Tkacheva
William J. Shufesky
Louis D. Falo
Adrian E. Morelli
Source :
The Journal of Immunology. 200:47.15-47.15
Publication Year :
2018
Publisher :
The American Association of Immunologists, 2018.

Abstract

T-cell receptor (TCR)-signaling triggers intracellular Ca2+ increase required for NFAT1/2-mediated IL-2 secretion. This pathway is necessary for thymocyte maturation and survival of activated T cells in secondary lymphoid organs (SLOs). In T cells, cellular Ca2+ levels are regulated by TCR- and G-protein coupled receptor (GPCR)-signaling via the PLCĪ³ and PLCĪ² subunits, respectively. Nevertheless, the GPCR(s) involved in this phenomenon has not been identified. The neurokinin-1 receptor (NK1R) is a GPCR that induces Ca2+ flux in neurons, and NK1R-signaling by the neuropetides substance P (SP) and hemokinin 1 (HK1) promotes T-cell immunity. We studied the role of NK1R-signaling in T-cell development in the thymus and after T-cell priming in SLOs. By Imagestream, we found that the NK1R and its ligands localize at the site of dendritic cell (DC)-T cell contact. Following CD3-signaling, the NK1R was required for optimal Ca2+flux and NFAT-mediated IL-2 secretion in T cells, effects that were abrogated in NK1RKO or SP/HK1double KO T cells. In the thymus, absence of NK1R resulted in decreased maturation and survival of TCR+ double positive CD4 CD8, single positive CD4, and single positive CD8thymocytes. In SLOs, the NK1R was required for survival of Ag-activated CD4 Th1 and CD8 T cells. In vivo, in a skin model of Th1-DTH induced in NK1RKO T-cell or HK-1/SPdouble KOT-cell bone marrow chimeras, 73±5% of activated CD4 and CD8 T cells died during priming in skin-draining SLOs, and the remaining T cells died in the skin following elicitation. We conclude that the NK1R cooperates with the TCR to increase intracellular Ca2+ necessary for thymocyte maturation and survival of activated T cells in SLOs. NIH R01 AR068249 and AR071277 to ATL and LDF.

Subjects

Subjects :
Immunology
Immunology and Allergy

Details

ISSN :
15506606 and 00221767
Volume :
200
Database :
OpenAIRE
Journal :
The Journal of Immunology
Accession number :
edsair.doi...........49242e76b1f1484a373faac489fda941