Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

• Published in: Science advances 2023-03, Vol.9 (12), p.eadf0567
• Main Authors: Hess, Nicholas J, Turicek, David P, Riendeau, Jeremiah, McIlwain, Sean J, Contreras Guzman, Emmanuel, Nadiminti, Kalyan, Hudson, Amy, Callander, Natalie S, Skala, Melissa C, Gumperz, Jenny E, Hematti, Peiman, Capitini, Christian M
• Format: Article
• Language: English
• Subjects: Animals; Biomedicine and Life Sciences; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes - pathology; Cell Biology; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunology; Mice; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adf0567

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 ≥ 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 naïve 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.