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 Vα14Jα18 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 Jα18 ^-/- BM cells show attenuation of GVHD, whereas recipients given CD1d^-/- BM cells did not show attenuation. Moreover, coinjection of BM non-Vα14Jα18 CD1d-restricted (type II) NKT cells and CD1d ^-/- BM cells suppressed GVHD, whereas coinjection of BM Vα14Jα18 TCR (type I) NKT cells did not. These protective effects on GVHD depended upon IFN-γ-producing type II NKT cells, which induced the apoptosis of donor T cells. The splenocytes of mice administered BM cells from B6.IL-4^-/- or Jα18^-/-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-γ^-/-, Jα18^-/-, or Jα18^-/-IFN-γ^-/- mice. Taken together, our results show that IFN-γ-producing BM type II NKT cells suppress GVHD by inducing the apoptosis of donor T cells, while IL-4-producing BM type II NKT cells protect against GVHD by deviating the immune system toward a Th2-type response.