Specific donor Vβ-associated CD4 + T-cell responses correlate with severe acute graft-versus-host disease directed to multiple minor histocompatibility antigens

Abstract

CXB-2/By (CXB-2) recombinant inbred mice express a subset of the minor histocompatibility antigen (miHA) repertoire expressed by C.B10-H2 b/LiMcdJ (BALB.B) mice. On lethal irradiation and the transplantation of H2 b-matched C57BL/6 (B6) T cell-depleted bone marrow cells, along with naive unfractionated T cells, both strains succumb to acute graft-versus-host disease (GVHD). Although alloreactive B6 CD4 + T cells are a necessary source of T-cell help for the B6 CD8 + component of the GVHD response in both recipient strains, they are capable of mediating severe GVHD by themselves only in BALB.B mice. Previous CD4 + T-cell receptor repertoire analysis demonstrated overlapping oligoclonal Vβ use between the CD4 + B6 anti-BALB.B and B6 anti-CXB-2 responses, with indications of additional BALB.B unique T-cell responses (Vβ2 and Vβ11). We report here that the more severe B6 anti-BALB.B response is not due to a quantitative difference in the responding cells, because the frequency of alloreactive donor CD4 + T cells over time was equivalent in the spleens of BALB.B versus CXB-2 recipients. The responses were also similar in the number of infiltrating B6 CD4 + T cells in the lingual epithelium of the 2 recipients. In contrast, a significantly greater degree of infiltration and injury of BALB.B intestinal epithelium correlated with the increased level of clinical GVHD severity. Of most significance, despite the involvement of at least 11 Vβ-associated CD4 + T-cell families in the overall B6 anti-BALB.B response, the development of severe GVHD correlated with the presence of Vβ2- and Vβ11-positive donor T cells. Transplantation of donor CD4 + T cells from Vβ-associated families that were shared between the B6 anti-BALB.B and anti-CXB-2 responses resulted in minimal GVHD potential. These data suggest that severe GVHD across miHA barriers depends on the involvement of a restricted number of potent T-cell specificities and implies that there are only a limited number of corresponding responsible miHAs.