Donor bone marrow type II (Non-Vα14Jα18 CD1d-restricted) NKT cells suppress graft-versus-host disease by producing IFN-γ and IL-4

NKT cells in donor bone marrow (BM) have been demonstrated to protect against graft-vs-host disease (GVHD) following BM transplantation. Murine NKT cells are divided into two distinct subsets based on the invariant V alpha 14J alpha 18 TCR expression. However, details of the subset and mechanisms of the BM NKT cells involved in suppressing GVHD have not been clarified. Irradiated BALB/c or C3H/HeN mice administered B6 or J alpha 18(-/-) BM cells show attenuation of GVHD, whereas recipients given CDld(-/-) BM cells did not show attenuation. Moreover, coinjection of BM non-V alpha 14J alpha 18 CDld-restricted (type 11) NKT cells and CDld(-/-) BM cells suppressed GVHD, whereas coinjection of BM V alpha 14J alpha 18 TCR (type 1) NKT cells did not. These protective effects on GVHD depended upon IFN-y-producing type 11 NKT cells, which induced the apoptosis of donor T cells. The splenocytes of mice administered BM cells from B6.IL-4(-/-) or J alpha 18(-/-)IL-4(-/-) mice produced lower levels of IL-4 and IL-10 than the splenocytes of mice transplanted with BM cells from B6, B6.IFN-gamma(-/-), J alpha 18(-/-), or J alpha 18(-/-)IFN-gamma(-/-) mice. Taken together, our results show that IFN-gamma-producing BM type 11 NKT cells suppress GVHD by inducing the apoptosis of donor T cells, while IL-4-producing BM type 11 NKT cells protect against GVHD by deviating the immune system toward a Th2-type response.