Repertoire Analysis of CD8+ T Cell Responses to Minor Histocompatibility Antigens Involved in Graft-Versus-Host Disease

Abstract

AbstractGraft-vs-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Experimentally, lethal GVHD can be induced in MHC-matched strain combinations differing in expression of multiple minor histocompatibility Ags (miHA). Recently, the GVHD potential of C57BL/6By (B6) T cells in irradiated BALB.B (both H2b) and related CXB recombinant inbred strains of mice has been studied to determine the scope of the response to miHA in vivo and how it compared with CTL responses to immunodominant miHA in vitro. The GVHD response in these strain combinations appeared to be limited to a few Ags, yet there was no correlation of these miHA with that of in vitro CTL responses. To further investigate the role of CD8+ T cells in GVHD, we analyzed positively selected miHA-specific donor CD8+ thoracic duct lymphocytes (TDL) collected from irradiated BALB.B and CXBE mice, 5 to 6 days after transplantation of B6 T cells. Flow cytometric analysis of B6→BALB.B TDL did not indicate expansion of any particular TCR Vβ family, whereas Vβ10 and Vβ14 families were significantly expanded in the B6->CXBE TDL. However, PCR-based complementarity-determining region 3 size spectratyping revealed overlapping involvement of donor Vβ1, 6, 8, 9, 10, and 14 families in both BALB.B and CXBE recipients and unique utilization of the Vβ4 family in BALB.B mice, suggesting oligoclonal T cell responses to a limited number of miHA. In addition, the injection of CD8+Vβ14+ B6 T cells into irradiated BALB.B and CXBE mice induced lethal GVHD, confirming the involvement of miHA-specific T cells within an individual Vβ family.