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Mapping of Quantitative Trait Loci Determining NK Cell-Mediated Resistance to MHC Class I-Deficient Bone Marrow Grafts in Perforin-Deficient Mice¹

Maria H. Johansson^2,3,*,, Mesha A. Taylor^3,*, Maja Jagodic, Katalin Tus, John D. Schatzle^*, Edward K. Wakeland and Michael Bennett^*

^* Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, Tumor and Cell Biology and Strategic Research Center for Studies of Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden; and Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390

NK cells reject allogeneic and MHC class I-deficient bone marrow (BM) grafts in vivo. The mechanisms used by NK cells to mediate this rejection are not yet thoroughly characterized. Although perforin plays a major role, perforin-independent mechanisms are involved as well. C57BL/6 mice deficient in perforin (B6 perforin knockout (PKO)) reject class I-deficient TAP-1 KO BM cells as efficiently as normal B6 mice. In contrast, perforin-deficient 129S6/SvEvTac mice (129 PKO) cannot mediate this rejection while normal 129 mice efficiently reject. This suggests that in 129, but not in B6, mice, perforin is crucial for NK cell-mediated rejection of MHC class I-deficient BM grafts. To identify loci linked to BM rejection in perforin-deficient mice, we generated backcross 1 progeny by crossing (129 x B6)F₁ PKO mice to 129 PKO mice. In transplantation experiments, >350 backcross 1 progeny were analyzed and displayed a great variation in ability to reject TAP-1 KO BM grafts. PCR-based microsatellite mapping identified four quantitative trait loci (QTL) on chromosomes 2, 4, and 8, with the QTL on chromosome 8 showing the highest significance, as well as a fifth epistatic QTL on chromosome 3. This study describes the first important step toward identifying BM graft resistance gene(s).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants CA36922, CA70134, and AI38938. M.H.J. was supported by a postdoctoral fellowship from the Swedish Cancer Society and by grants from Karolinska Institutet, the Åke Wiberg Foundation, the Magnus Bergwall Foundation, the Royal Swedish Academy of Sciences, and the Swedish National Board of Health and Welfare.

² Address correspondence and reprint requests to Dr. Maria H. Johansson, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, SE-17177 Stockholm, Sweden. E-mail address: maria.johansson{at}ki.se

³ M.H.J. and M.A.T. contributed equally to the study.

⁴ Abbreviations used in this paper: BM, bone marrow; KO, knockout; PKO, perforin KO; wt, wild type; QTL, quantitative trait locus; ₂m, ₂-microglobulin; BC, backcross; LOD, logarithm of odds; bmgr, bone marrow graft rejection; NKC, NK gene complex; PLC, phospholipase C; PKC, protein kinase C; MMP, matrix metalloproteinase; GBP, guanylate-binding protein.