Identification and function of a CD4+/CD8αβ+ T cell population that is predictive of GVHD development in a xenogeneic transplant model

Abstract

Abstract Graft-vs-host disease (GVHD) is mediated by donor reactive T cells that have a hierarchical classification based on CD4 and CD8 expression. While CD4 and CD8 lineages are thought to have fixed expression, CD4+/CD8αβ+ double positive (DP) T cells have been reported in cases of human cancers and autoimmune diseases though the lack of a suitable model system has hindered their research. In this study, we transplanted primary human graft tissue into non-conditioned immunodeficient mice and observed the development of a human DP T cell population that was not present in the starting grafts. This DP T cell population developed irrespective of graft tissue (peripheral blood, bone marrow or umbilical cord blood), accessory cells (transplantation with isolated T cells) and immunodeficient mouse strain (NSG and NBSGW). Furthermore, an increase in the percentage of DP T cells in the blood of these mice is correlated and predictive of GVHD development. We also observed that DP T cells are functionally active with significantly elevated IFNγ and TNFα secretion compared to CD4 and CD8 single positive T cells. DP T cell also display elements of the cytotoxic machinery including NKG2D and perforin/granzyme expression. Interestingly, transplantation of isolated CD4+ cells did not result in the development of DP T cells while a robust population developed after transplantation of isolated CD8+ T cells. DP T cells were also identified in primary clinical samples taken from HSCT patients with their clinical relevance to GVHD currently under investigation. In conclusion, this ongoing study has identified a novel human DP T cell that arises from the CD8+ T cell population, is functional active and is predictive of GVHD in a xenogeneic transplant model.