Donor CD4⁺ T Cells That Possess Both Allo- and Autoreactivity in Transplants Mediate Chronic Graft Versus Host Disease.

Abstract 3555

Poster Board III-492

Chronic graft versus host disease (GVHD) is considered an autoimmune-like disease mediated by donor CD4⁺ T cells, but the role and origin of the autoreactive T cells remain controversial. Here, we report that, in a chronic GVHD model of MHC-matched DBA/2 (H-2^d) donor to BALB/c (H-2^d) host, donor spleen cells induced autoimmune-like chronic GVHD in thymectomized allogeneic BALB/c but not in syngeneic DBA/2 recipients. The spleen cells from the former but not the latter recipients induced autoimmune-like disease in the secondary DBA/2 recipients, indicating that autoreactive donor CD4⁺ T cells from transplants are expanded and contribute to chronic GVHD pathogenesis. In addition, we found that both auto- and alloreactive donor CD4⁺ T cells generated from primary chronic GVHD recipients via serial in vivo and in vitro expansion proliferated to donor and host DC stimulation and both induced autoimmune-like disease in syngeneic and allogeneic recipients. Furthermore, the clonal expansion and TCR spreading of the autoreactive T cells in chronic GVHD recipients were following the alloreactive T cells, as revealed by TCR-spectrum typing and skewing of TCR-CDR3 length; No dual TCR was expressed by the donor-type T cells with both allo- and autoreactivity; and the autoreactive hybridoma T clones proliferated to stimulation by both syngeneic and allogeneic DCs. Taken together, these results demonstrate that donor CD4⁺ T cells that possess both allo- and autoreactivity in transplants are expanded in recipients and contribute to chronic GVHD pathogenesis, and the allo- and autoreactivity of the donor T cells can be mediated by a single TCR.