CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT.
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 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.
Johnson
Bryon D
BD
Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226, USA. bjohnson@mcw.edu
Konkol
Marja C
MC
Truitt
Robert L
RL
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000502:physiology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007108:Immune Tolerance; D017710:Lymphocyte Transfusion; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000235:genetics; D014184:Transplantation, Homologous
D018106:CD28 Antigens; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand