Author:
Wang Shaoxun,Song Guiyu,Barkestani Mahsa Nouri,Tobiasova Zuzana,Wang Qianxun,Jiang Quan,Lopez Roberto,Adelekan-Kamara Yasmin,Fan Matthew,Pober Jordan S.,Tellides George,Jane-wit Dan
Abstract
IntroductionIschemia reperfusion injury (IRI) confers worsened outcomes and is an increasing clinical problem in solid organ transplantation. Previously, we identified a “PtchHi” T-cell subset that selectively received costimulatory signals from endothelial cell-derived Hedgehog (Hh) morphogens to mediate IRI-induced vascular inflammation.MethodsHere, we used multi-omics approaches and developed a humanized mouse model to resolve functional and migratory heterogeneity within the PtchHi population. ResultsHh-mediated costimulation induced oligoclonal and polyclonal expansion of clones within the PtchHi population, and we visualized three distinct subsets within inflamed, IRI-treated human skin xenografts exhibiting polyfunctional cytokine responses. One of these PtchHi subsets displayed features resembling recently described T peripheral helper cells, including elaboration of IFN-y and IL-21, expression of ICOS and PD-1, and upregulation of positioning molecules conferring recruitment and retention within peripheral but not lymphoid tissues. PtchHi T cells selectively homed to IRI-treated human skin xenografts to cause accelerated allograft loss, and Hh signaling was sufficient for this process to occur. DiscussionOur studies define functional heterogeneity among a PtchHi T-cell population implicated in IRI.
Subject
Immunology,Immunology and Allergy