Bone marrow NK1.1^- and NK1.1⁺ T cells reciprocally regulate acute graft versus host disease

Sorted CD4⁺ and CD8⁺ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2(b)) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell-depleted donor marrow cells, into lethally irradiated BALB/c (H-2(d)) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1⁺ T cells represented <1% of all T cells in the blood and ~30% of T cells in the marrow, the capacity of sorted marrow NK1.1^- CD4⁺ and CD8⁺ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1⁺ T cells suppressed GVHD. The marrow NK1.1⁺ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1^- T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1⁺ T cells obtained from IL-4(-/-) rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1^- and NK1.1⁺ T cell subsets via their differential production of cytokines.