期刊
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
卷 8, 期 10, 页码 525-535出版社
CARDEN JENNINGS PUBL CO LTD
DOI: 10.1053/bbmt.2002.v8.pm12434947
关键词
donor leukocyte infusion; bone marrow transplantation; regulatory T-cells; graft-versus-host disease
资金
- NCI NIH HHS [CA39854, CA90286] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA090286, R01CA039854] Funding Source: NIH RePORTER
We have previously identified donor-derived Thy1(+) alphabeta T-cell receptor (TCR)(+) CD4(+)CD8(-) regulatory T-cells that suppress GVH reactivity induced by donor leukocyte infusion (DLI) after BMT. These cells develop in the recipient thy-us and may play a role in the maintenance of donor-host tolerance after allogeneic BMT. In the present study, we sought to further characterize the T-cells responsible for the regulatory cell activity in our model. Lethally irradiated recipient AKR mice (H-2(k)) received transplants of BM from CD25-deficient (-/-) C57BL/6 mice (H-2(b)). Recipients of CD25-deficient BM developed more severe GVHD after DLI than did recipients of normal BM, a result that indirectly suggests that CD4(+)CD25(+) regulatory T-cells are important to the suppression of GVH reactivity after allogeneic BMT. GVHD was accompanied by mortality, body weight loss, and elevated percentages of T-cells from the DLI in the peripheral blood in mice that received CD25-deficient BM compared to mice that received normal BM. Both CD40-CD40L and CD28-B7 costimulatory pathways have been implicated in the generation of CD25(+) regulatory T-cells. Therefore, we tested whether deficiency in either of these pathways affected the activity of donor BM-derived regulatory T-cells. The absence of CD40L did not affect the regulatory T-cells (ie, recipient mice were still protected from DLI-induced GVHD). In contrast, use of marrow from CD28-deficient mice resulted in complete loss of suppression of GVH reactivity. Thus, CD28 but not CD40L was critical for the generation and/or activation of immunoregulatory T-cells that suppressed GVHD induced by DLI. Together, the results of these experiments suggest that CD4(+)CD25(+) regulatory T-cells suppress GVH reactivity after BMT and that CD28 expression is indispensable for the generation of these cells.
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