Role of immunodominant T cell responses to minor histocompatibility antigens in a mouse model of graft-versus-host disease

Graft-versus-host-disease (GVHD) is a major complication of major histocompatibility complex (MHC) matched bone marrow transplantation. GVHD is the result of an immune-mediated attack, by T lymphocytes derived from donor bone marrow, against recipient tissues expressing minor histocompatibility antigen (miHA) differences. There is a lack of knowledge concerning the nature of in vivo immune responses to miHA during GVHD. C57BL/6By(B6/By) and BALB.B mouse strains both express the H-2$\sp{\rm b}$ MHC haplotype but differ at more than 40 miHA loci. Both the in vitro and in vivo T cell responses to miHA expressed by BALB.B and CXB recombinant inbred (RI) strains of mice (CXBE, G, I, J and K) are governed by immunodominance. There are disparities between the hierarchies of in vitro and in vivo immunodominant T cell responses to BALB.B derived miHA. The focus of this thesis work was to investigate the nature of T cell responses to miHA in a mouse model of GVHD and to determine what role immunodominance had in GVHD responses. The first part of this work demonstrated that the discrepancy between in vitro and in vivo immunodominant T cell responses was not due to a differential requirement of T cell subsets. One hypothesis accounting for the discrepancy was that in vitro responses required CD8+ CTL while in vivo responses were mediated by the CD4+ T helper (Th) cell subset. Both CD4+ and CD8+ B6/By T cells were active in GVHD responses in BALB.B and all of the CXB RI strains. The second part of this work investigated the role of immunodominance in GVHD induction. MiHA-specific T cell blasts positively selected from thoracic duct lymphocytes (TDL) collected from BALB.B and CXBE mice injected with B6/By T cells were analyzed for V$\beta$ T cell receptor (TCR) usage. During the period of 4-6 days post-transplant, only CD4+ T cells exhibited noticeable shifts in expansion and V$\beta$ utilization. CD4+V$\beta$6+ and CD4+V$\beta$8.1,8.2+ T cells were selectively expanded in B6/By anti-BALB.B TDL. In contrast, B6/By anti-CXBE TDL contained expanded CD4+V$\beta$7+ and CD4+V$\beta$9+ T cells. The different TCR repertoires in the two strain combinations suggested that B6/By CD4+ T cells recognized differentially expressed immunodominant miHA during GVHD induction. Results of PCR-based spectratyping and cDNA sequencing of anti-BALB.B CD4+ TDL T cell V$\beta$6 TCR demonstrated CDR3 size skewing and biased usage of J$\beta$1.3 and J$\beta$2.4 gene segments. These results are evidence of oligoclonal expansion by miHA-specific effector CD4+ T cells during GVHD induction