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) 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 predominate over hematopoietic stem cell-derived T cells generated (T) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting T, in particular CD8 T, 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 in the reconstituted host. Selective depletion of T in the chronic phase of disease resulted in the expansion of T and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, T depletion caused activation of T and resulted in a lethal T-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting T in cGVHD.