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

• Published in: PloS one 2017-09, Vol.12 (9), p.e0184254-e0184254
• Main Authors: Hossain, Mohammad S, Kunter, Ghada M, El-Najjar, Vicky F, Jaye, David L, Al-Kadhimi, Zaid, Taofeek, Owonikoko K, Li, Jian-Ming, Waller, Edmund K
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Antigens; Apoptosis; Biology and Life Sciences; Bone marrow; Cancer; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Comparative analysis; Complications and side effects; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytokines; Dendritic cells; Disease; Foxp3 protein; Gene expression; Graft vs Host Disease - prevention & control; Graft vs. host disease; Graft-versus-host reaction; Hematology; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Immune checkpoint; Immune response; Immune response (cell-mediated); Immune system; Immunoglobulins; Immunology; Immunotherapy; Infections; Inflammation; Kinetics; Laboratory animals; Lymphocytes; Lymphocytes T; Medicine; Medicine and Health Sciences; Mice, Inbred BALB C; Mice, Inbred C57BL; Oncology; Organs; Patient outcomes; PD-1 protein; PD-L1 protein; Physiological aspects; Prevention; Programmed Cell Death 1 Receptor - metabolism; Risk factors; Rodents; Spleen; Stem cell transplantation; Stem cells; T cells; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0184254

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.