CD25+ immunoregulatory T-Cells of donor origin suppress alloreactivity after BMT

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Abstract

We have previously identified donor-derived Thy1+ αβ 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 thymus 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-2k) received transplants of BM from CD25-deficient (-/-) C57BL/6 mice (H-2b). 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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Johnson, B. D., Konkol, M. C., & Truitt, R. L. (2002). CD25+ immunoregulatory T-Cells of donor origin suppress alloreactivity after BMT. Biology of Blood and Marrow Transplantation, 8(10), 525–535. https://doi.org/10.1053/bbmt.2002.v8.pm12434947

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