CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection

• Type of Material: Article
• Authors: Jaclyn Espinosa, Emory University; Florence Herr, INSERM; Gregory Tharp, Emory University; Steven Bosinger, Emory University; Mingqing Song, Emory University; Alton Farris III, Emory University; Roshan George, Emory University; Jennifer Cheeseman, Emory University; Linda Stempora, Emory University; Robert Townsend, Bristol Myers Squibb Co; Antoine Durrbach, INSERM; Allan Kirk, Emory University
• Language: English
• Date: 2016-04-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.13613
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 16
• Issue: 4
• Start Page: 1102
• End Page: 1112
• Grant/Funding Information: This research was supported by a grant from Bristol-Myers Squibb and the National Institute of Allergy and Infectious Disease R01 A1097423 (ADK).
• Keywords: CYCLOSPORINE; BLOCKADE; Science & Technology; COSTIMULATION; DISEASE; TELOMERE LENGTH; Surgery; Transplantation; IMMUNOLOGICAL MEMORY; Life Sciences & Biomedicine; EXPRESSION; ACTIVATION; TRANSPLANT RECIPIENTS; IMMUNOSUPPRESSION
• Research Categories: Biology, Cell; Health Sciences, Pathology; Biology, Molecular

Abstract

Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57+PD1- CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57+ CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28-, expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57+ CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.