Alloreactive CD4 T lymphocytes responsible for acute and chronic graft-versus-host disease are contained within the CD45RChigh but not the CD45RClow subset

Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation and occurs when donor T cells react with histo-incompatible recipient's antigens. In the present study, we analyzed the contribution of CD4 T cell subsets, defined according to their CD45RC expression level, in the development of acute and chronic GvHD. For this purpose, we used the model of GvHD induced in rats when parental lymphocytes are transferred to irradiated (LEWxBN) F1 hybrid recipients. We showed that parental CD45RC(high) (naive cells) CD4 T cells induced both acute and chronic GvHD while CD45RC(low) (memory cells) subset did not. In vitro, only CD45RC(low) CD4 T cells proliferated and produced cytokines in response to alloantigen stimulation. LEW and BIN CD45RC(high) CD4 T cells produced different cytokine profiles in response to in vitro allostimulation, which could explain their ability to induce different forms of GvHD. Finally, we showed that memory CD45RC(low) CD4 T cells, known to contain regulatory T cells, were unable to prevent GvHD induction. Together these data show that memory CD45RC(high) CD4 T cells do not contain functional alloreactive T cells and suggest that selective transfusion of donor memory cells could greatly improve post-transplant immune reconstitution without risk of GvHD induction.