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.