Noriko Arase

Influence of graft versus host reaction on the T cell repertoire differentiating from bone marrow precursors following allogeneic bone marrow transplantation

When lethally irradiated AKR (Mls-1a) mice were reconstituted with bone marrow (BM) cells plus a small number (0.5%) of mature T cells from allogeneic B10.AQR or B10 (Mls-1b) mice and minor GVHR was induced in the recipients, almost complete donor chimerism was accomplished in the early stages after reconstitution. By contrast, in irradiated AKR mice reconstituted with T cell-depleted BM cells alone from B10 or B10.AQR mice, radio-resistant T cells of recipient origin persisted for a relatively long period in peripheral lymphoid tissues. In this paper the influence of residual T cells in the chimeric mice on generation of the T cell repertoire derived from donor BM is discussed. It will be demonstrated that the recipient (AKR) T cells are capable of producing Mls-1a antigens (Ag) after lethal irradiation in vivo. These recipient T cells eventually induce clonal elimination of Mls-1a reactive V beta 6+, V beta 8.1+ and V beta 9+ T cells derived from developing thymocytes of donor BM origin. The Mls-1a reactive T cells are not eliminated in GVHR chimeras in which recipient T cells are absent. However, V beta 5+ T cells reactive to I-E plus Etc-1 Ag are deleted in the chimeras undergoing GVHR. These results indicate that recipient cells which produce tissue-specific antigens (tolerogens) should be taken into consideration when generation of the T cell repertoire of donor origin following allogeneic BM transplantation is investigated.

Production of Minor Lymphocyte Stimulatory-1a Antigens from T Cell Subsets

T cell subsets that produce minor lymphocyte stimulatory (Mls) antigens were analyzed using mixed lymphocyte reaction (MLR) in vitro or clonal elimination assay in vivo. When lymph node T cells from B10.BR(Mls-1b) mice were stimulated with various T cell subsets from AKR (Mls-1a) mice in the presence of B10.BR antigen presenting cells (APC), proportions of Mls-1a reactive T cell blasts (V beta 6+, V beta 8.1+) increased. The stimulatory potency of CD8+ T cells was higher than that of CD4+ T cells. Furthermore, among either CD8+ or CD4+ T cell subset, CD44+ T cells appeared to produce larger amounts of Mls-1a antigens than CD44- T cells. More marked difference was demonstrated, when stimulator AKR T cells were being activated by immobilized anti-T cell antigen receptor (TCR) antibody during MLR. Thus, AKR T cells appeared to produce large amounts of Mls-1a antigens on appropriate stimulations. These findings were confirmed by the semiquantitative analysis of mRNA levels of MTV-7 in the AKR T cell subsets. When CD8+CD44+ T cells from (AKR x B10.BR)F1 mice were injected intravenously into [B10.BR-->B10.BR] syngeneic bone marrow (BM) chimeras 1 week after BM reconstitution and proportions of V beta 6+ T cells were quantitated 7 weeks later, significant clonal elimination of V beta 6+ T cells was induced among both thymocyte population and lymph node T cell population in a dose-dependent manner of the inoculated F1 T cells. Inoculation of CD8+CD44-F1 T cells eliminated V beta 6+ T cells less efficiently from lymph node T cells and inoculation of CD4+F1 T cells induced no significant clonal elimination of the V beta 6+ T cells. The present findings demonstrate clearly that CD8+CD44+ T cells represent the cells producing large amounts of Mls-1a antigens and inducing clonal elimination of V beta 6+ T cells in vivo.