Hedgehog costimulation during ischemia-reperfusion injury potentiates cytokine and homing responses of CD4+ T cells

Frontiers in Immunology

Immunology

Dan Jane-wit¹  Qianxun Wang¹  Quan Jiang¹  Mahsa Nouri Barkestani¹  Guiyu Song²  Shaoxun Wang³  Zuzana Tobiasova⁴  Jordan S. Pober⁴  Matthew Fan⁴  George Tellides⁵  Yasmin Adelekan-Kamara⁶  Roberto Lopez⁷ 

[1] Department of Cardiology, West Haven Veterans Affairs (VA) Medical Center, West Haven, CT, United States;Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States;Department of Cardiology, West Haven Veterans Affairs (VA) Medical Center, West Haven, CT, United States;Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States;Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China;Department of Cardiology, West Haven Veterans Affairs (VA) Medical Center, West Haven, CT, United States;Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States;Department of Surgery, Yale University School of Medicine, New Haven, CT, United States;Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States;Department of Surgery, Yale University School of Medicine, New Haven, CT, United States;Faculty of Medicine, Imperial College, London, United Kingdom;Yale College, Yale University, New Haven, CT, United States;

关键词: ischemia-reperfusion (I/R) injury;    alloimmune;    T cell;    hedgehog;    humanized model mouse;   

DOI  :  10.3389/fimmu.2023.1248027

 received in 2023-06-26, accepted in 2023-09-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Wang, Song, Barkestani, Tobiasova, Wang, Jiang, Lopez, Adelekan-Kamara, Fan, Pober, Tellides and Jane-wit