Cytokine and cytotoxic pathways of NK cell rejection of class I- deficient bone marrow grafts: influence of mouse colony environment

Mouse NK cells may use both cytokine, e.g. IFN-gamma, tumor necrosis factor (TNF)-alpha and IL-12, and cytotoxic, e.g. perforin and Fas-FasL, pathways to reject incompatible bone marrow cell (BMC) grafts. To begin a dissection of these two major pathways, mice bearing deletional mutations of IFN-gamma, TNF-RI/II or perforin, or mice treated with mAb to IL-12, IFN-gamma or NK1.1 were irradiated and challenged with class I-deficient BMC grafts, a system in which only NK cells are the effector cells. Proliferation of the donor-derived cells was judged in terms of splenic incorporation of [125I]iododeoxyuridine 5 or 7 days after cell transfer. All of these mice maintained in a specific pathogen-free (s.p.f.) environment were able to reject the BMC, except those treated with anti-NK1.1 mAb. However, perforin deficient mice maintained in a conventional breeding facility failed to reject class I (Tap-1)-deficient marrow cells. Transfer of mice from the pathogen-free to the conventional facility resulted in a slow and incomplete loss of the ability to reject marrow cells. Thus, the breeding colony environment can elicit otherwise undetectable defects in the rejection ability of perforin-deficient NK cells. This report will hopefully alert those investigators who have only studied immune gene knockout mice in s.p.f. facilities and found no significant abnormalities.