Focusing on identifying T cells responsible for GVHD pathology, Hess et al. analyzed a cohort of 35 patients who received allogeneic hematopoietic cell transplants and showed that CD4+/CD8+ double-positive T cells (DPT) correlated with ≥ grade 2 GVHD, but were absent in the initial graft. In a xenogeneic transplant model, DPT cells arose from antigen-stimulated CD8+ T cells and were transcriptionally, metabolically, and phenotypically distinct from single-positive CD4+ and CD8+ T cells. Isolated DPTs were sufficient to drive xeno-GVHD pathology without providing a survival benefit when transplanted into naive mice, suggesting DPTs may play a direct role in GVHD pathology.
Contributed by Katherine Turner
ABSTRACT: An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4(+)/CD8(+) double-positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ³ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develops from antigen-stimulated CD8 T cells, which become transcriptionally, metabolically, and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when retransplanted into nave mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.
Author Info: (1) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Department of Medicine, University of Wisconsin School of Medicine and
Author Info: (1) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. University of Wisconsin Carbone Cancer Center, Madison, WI, USA. (2) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. (3) Morgridge Institute for Research, Madison, WI, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. (4) University of Wisconsin Carbone Cancer Center, Madison, WI, USA. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA. (5) Morgridge Institute for Research, Madison, WI, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. (6) Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. University of Wisconsin Carbone Cancer Center, Madison, WI, USA. (7) Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. (8) Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. (9) Morgridge Institute for Research, Madison, WI, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. (10) University of Wisconsin Carbone Cancer Center, Madison, WI, USA. Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. (11) Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. University of Wisconsin Carbone Cancer Center, Madison, WI, USA. (12) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
