Long-Lasting Graft-Derived Donor T Cells Contribute to the pathogenesis of Chronic Graft-versus-Host Disease in Mice

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (T-G) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that T-G predominate over hematopoietic stem cell-derived T cells generated de novo (T-HSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting T-G, in particular CD8(+) T-G, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of T-G in the reconstituted host. Selective depletion of T-G in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of T-G and resulted in a lethal T-G-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting T-G in cGVHD.