The role of NK1.1S+ cells and TH1 cytokines in the pathogenesis of acute murine graft-versus-host disease (GVHD)

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Ellison, Cynthia A.
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Previous studies using a murine F1-hybrid model of acute GVHD have shown that mortality is prevented if the graft is depleted of NK1.1 + cells. The precise role played by these cells in the pathogenesis of GVHD has not been elucidated, but it is thought that they injure host target tissues. Two cytotoxic, NK1.1+ subpopulations are activated during acute GVH reactions: conventional NK cells that lyse NK-sensitive targets, and NK-like cells that lyse both NK-sensitive and -resistant targets. Because the latter is derived largely from the donor, we hypothesized that it may be particularly important in the pathogenetic mechanism. However, because there is also evidence that some NK1.1+ cells have immunoregulatory function, we further postulated that some NK1.1+ cells promote the early Th1 response that underlies derlies development of acute GVHD. Experiments were performed to determine whether (a) _[delta]T cells mediate NK-like activity and are required for acute GVHD to occur; (b) depleting the graft of NK1.1+ cells mitigates the development of a Th1-mediated immune response (c) eliminating donor-derived IFN-_ influences the outcome of the disease. Results showed that the NK-like cells express _[delta]TCR, and removing them partially protects recipients against mortality. However, the use of TCR[delta] (knockout) KO grafts was not protective, and IFN-_ levels were higher. The Th1 response, as measured by IFN-_ production and LPS-induced TNF_ release, was abrogated in recipients of NK1.1-depleted grafts, but intestinal lesions and high serum LPS levels still developed. GVHD in recipients of IFN-_ KO grafts was lethal, but more protracted, resembling chronic GVHD. NK1.1 depletion of these grafts was protective. In summary, _[delta]T cells contribute to the demise of GVH mice, but other cells are also involved. In wild-type graft recipients, the protection conferred by NK 1.1 graft depletion results from factors other than, or in addition to, abrogated IFN-_ production, which appears to accelerate mortality. The gut injury seen in these mice is mediated by cells other than those in the graft expressing NK1.1. We postulate that these are donor-derived _[delta]T cells.