T-cell receptor Valpha spectratype analysis of a CD4-mediated T-cell response against minor histocompatibility antigens involved in severe graft-versus-host disease.

Although CD4(+) T cells can have an important role in mediating lethal graft-versus-host disease (GVHD) directed to multiple minor histocompatibility antigens (miHA) after bone marrow transplantation, their precise characterization and effector function remains elusive. In this regard, T cell receptor (TCR) Vbeta spectratype analysis has been a powerful tool for identifying donor CD4(+) T cell populations expanding to host miHA after bone marrow transplantation in the major histocompatibility complex-matched C57BL/6 (B6) --> C.B10-H2(b) (BALB.B) model of lethal GVHD. Removal of all of the Vbeta(+) T cell families containing these responding cells from the donor inoculum has proven to be an effective means of preventing the development of GVHD. Previous studies have also found that of the 11 miHA-responsive B6 CD4(+) Vbeta(+) T cell families, transplantation of Vbeta2(+) and Vbeta11(+) T cells together into lethally irradiated BALB.B mice appeared to be primarily responsible for the severity of resultant GVHD. Further focusing on these critical CD4 responses, in this study we demonstrate that B6 CD4(+)Vbeta11(+) T cells alone can induce lethal GVHD in BALB.B recipients. In addition, immunohistochemical staining of host lingual and intestinal epithelial tissues supported the capacity of Vbeta11(+) T cells to infiltrate typical GVHD-associated target areas. To further characterize the specific CD4(+)Vbeta11(+) T cells involved in this anti-miHA response, TCR Valpha spectratype analysis was performed and indicated that 6 Valpha chains were used by this reactive population. These results provide further evidence that a restricted repertoire of T cell specificities, presumably recognizing a correspondingly low number of miHA, is sufficient for the induction of severe GVHD.