The success of allogeneic bone marrow transplantation (BMT) is dependent upon the establishment of durable engraftment and the amelioration of toxicity from graft-versus-host disease (GVHD). T cells in the donor graft are thought to be primarily responsible for facilitating alloengraftment, but they also play a major role in the initiation of GVHD. The predominant T-cell population which is implicated in each of these processes are alpha-beta+ T cells, while the immunological role of T cells which express the gamma-delta T-cell receptor is unknown. Gamma-delta+ T cells possess both functional and phenotypic differences relative to alpha-beta T cells, suggesting that they may play a novel and nonredundant role in marrow transplantation. The overall objective of these studies, therefore, is to evaluate the role of gamma-delta T cells in the context of alloengraftment and GVHD. It is the applicant's hypothesis that gamma-delta T cells are capable of promoting allogeneic marrow engraftment without augmenting GVH reactivity. The mechanism(s) by which gamma-delta T cells promote engraftment, however, and the extent to which this parallels how alpha-beta T cells facilitate engraftment is unknown. To critically evaluate these issues, the applicant has developed a murine transplant model in which donor and recipient are mismatched at the major histocompatibility complex (MHC) and in which simultaneous risks of graft rejection and GVHD are operative. Using this model, experiments will be designed to address the following Specific Aims: 1) to determine whether gamma-delta T cells directly prevent graft rejection, 2) to assess whether gamma-delta T cells require help from alpha-beta T cells to facilitate alloengraftment, 3) to determine if facilitation of alloengraftment by gamma-delta T cells is mediated by direct recognition of host alloantigens. The precise evaluation of the role of gamma-delta T cells in allogeneic BMT is critically dependent upon the ability to purify alpha-beta and gamma-delta T cell sub-populations. To this end, the proposed studies will make use of transgenic donors in which segments of the murine T-cell receptor beta chain or delta chain genes have been deleted by gene targeting. Thus, the use of alpha-beta and gamma-delta knockout mice as donors will allow the functional role of each T-cell subset to be selectively assessed in the proposed experiments. The long-term objective of these studies is that the functional understanding of the role of gamma-delta T cells in marrow transplantation can be applied to simultaneously reduce the risk of graft failure and GVHD.
