PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

• Type of Material: Article
• Authors: Mohammad Hossain, Emory University; Ghada M. Kunter, Holzer Cancer Center; Vicky F. El-Najjar, Emory University; David L. Jaye, Emory University; Zaid Al-Kadhimi, Emory University; Owonikoko K. Taofeek, Emory University; Jian-Ming Li, Emory University; Edmund K. Waller, Emory University
• Language: English
• Date: 2017-09-27
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Hossain et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0184254
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 12
• Issue: 9
• Start Page: e0184254
• End Page: e0184254
• Grant/Funding Information: This research was supported by NIH grant (R01 CA188523) to E.K.W.
• Keywords: Cytotoxic T cells; Host cells; Transplantation immunology; Inflammation; T cells; Cytokines; Spleen; Regulatory T cells
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.