Inter-strain graft-vs.-host disease T-cell responses to immunodominant minor histocompatibility antigens

Abstract

Immunodominance affects the in vitro generation of cytotoxic T lymphocytes (CTL) specific for minor histocompatibility antigens (miHA), as exemplified in the C57BL/6By (B6) anti-BALB.B H2b-matched strain combination. Despite the potential of responding to numerous individual miHA on BALB.B antigen presenting cells, the focus of the CTL response is largely directed to only a limited number of target antigens. These miHA are differentially expressed by the CXBE, CXBG, CXBI, CXBJ, and CXBK recombinant inbred (RI) strains, all of which also express the H2b MHC haplotype. Immunodominance also plays a role in the development of lethal graft-vs.-host disease (GVHD) directed to miHA, by which B6 T cells were transplanted along with T-cell depleted bone marrow to irradiated (825 cGy) recipients of either the BALB.B or CXB RI strains. The hierarchy of immunodominance differed in GVHD from that predicted from the in vitro CTL studies; i.e., GVHD was observed in BALB.B, CXBE, CXBI, and CXBJ recipients, but not in CXBG and CXBK recipients, despite the latter two strains expressing immunodominant antigens for CTL generation. Interpretation of these results was complicated by the finding that potent GVHD could be obtained with the transfer of CXBE T cells and ATBM to irradiated CXBG recipients. To clarify the scope of the inter-strain immunodominant interactions involved in GVHD in these strain combinations and to estimate the minimum number of miHA that could be responsible for GVHD, a full panel of GVHD responses was analyzed. The GVHD potential was evaluated for donor T cells derived from both parental RI strains as well as for (B6 x RI)F1 hybrids to restrict responses to only those miHA originating from BALB.B origin. The results were consistent with the minimal involvement of two distinct immunodominant miHA in the B6-->BALB.B lethal GVHD response. One immunodominant miHA (GVH-1) appeared to be shared by the CXBE, CXBI, and CXBJ RI strains, while the second antigen (GVH-2) was uniquely expressed by the parental BALB.B strain.