Neurokinin-1 Receptor-Signaling of T Cells and Dendritic Cells Is Required for Optimal Elicitation of the T-Cell Response That Leads to Graft Rejection
Dept. of Surgery, T.E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Dept. of Dermatology, University of Pittsburgh, Pittsburgh, PA
Meeting: 2013 American Transplant Congress
Abstract number: A729
Increasing evidence suggests that elicitation of donorreactive T-cell immunity is regulated by pro-inflammatory neuropeptides. Substance P (SP) is the prototypic pro-inflammatory neuropeptide released by leukocytes and nerves that promotes innate and adaptive immunity by binding the Neurokinin-1 Receptor (NK1R) expressed by dendritic cells (DC) and T cells. Aim: we investigated the mechanisms by which mice lacking the NK1R exhibit impaired allo-DTH responses and delayed allograft rejection. Methods: Allo-DTH was assessed in wt or NK1RKO B6 mice sensitized (footpad) with BALB/c bone marrow (BM) DC. SP was detected by RT qPCR and fluorescence microscopy. The stimulatory capacity of NK1RKO DC and T-cell responses were assessed (i) in vitro: in CFSE-MLC, and (ii) in vivo: in CFSE-TCR tg 1H3.1 CD4 T cells [specific for (BALB/c) IEΑ52-68 -(B6) IAb ] transferred into wt or NK1RKO B6 mice skin-sensitized of grafted with BALB/c skin 1 d later. Detection of translocation of transcription factors was done by SDS-PAGE and Western blot. Results: The cutaneous allo-DTH response was abrogated in NK1RKO mice, with minimal skin infiltration of macrophages and T cells, compared to wt controls. NK1RKO B6 mice also rejected BALB/c skin grafts with delayed tempo. Traffic studies indicated that this was not due to inability of skin NK1RKO DC to migrate to the draining lymph nodes. However, NKR1KO DC secreted significantly lower levels of IL-12p70 and higher amounts of IL-10 and TGF-Β1 and therefore were deficient at polarizing type-1 T cells in vitro and in vivo, the latter assessed in adoptively transferred CFSE-labeled 1H3.1 CD4 T cells. On the other hand, NK1RKO T cells proliferated as efficiently as wt cells, but died by apoptosis due to their low IL-2RΑ expression, IL-2 secretion and Bcl-2 content. Activated NK1RKO T cells exhibited reduced nuclear translocation of the IL-2 transcription factors NFAT1c and NFAT2c. Conclusions: After allo-sensitization, NK1R-signling via pro-inflammatory neuropeptides is critical for generation of type-1 polarizing DC and for nuclear translocation of NFAT1c and NFAT2c in T cells, the latter necessary for T-cell survival.
To cite this abstract in AMA style:
Rojas-Canales D, Shufesky W, Tkacheva O, Sumpter T, Larregina A, Morelli A. Neurokinin-1 Receptor-Signaling of T Cells and Dendritic Cells Is Required for Optimal Elicitation of the T-Cell Response That Leads to Graft Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/neurokinin-1-receptor-signaling-of-t-cells-and-dendritic-cells-is-required-for-optimal-elicitation-of-the-t-cell-response-that-leads-to-graft-rejection/. Accessed December 13, 2024.« Back to 2013 American Transplant Congress