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Global Unresponsiveness as a Mechanism of Natural Killer Cell Tolerance in Mixed Xenogeneic Chimeras
Author(s) -
Kawahara T.,
RodriguezBarbosa J.I.,
Zhao Y.,
Zhao G.,
Sykes M.
Publication year - 2007
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2007.01905.x
Subject(s) - medicine , mechanism (biology) , immunology , chimera (genetics) , immune tolerance , microbiology and biotechnology , immune system , biology , genetics , gene , philosophy , epistemology
Mixed xenogeneic chimerism induces T‐ and B‐cell tolerance in mice receiving T‐cell‐depleted rat bone marrow cells (BMC) following nonmyeloablative conditioning that includes αβ and γδ T cell and Natural killer (NK) cell‐depleting mAbs. NK‐cell depletion is essential to permit marrow engraftment, but NK‐cell tolerance has not been previously assessed in mixed xenogeneic chimeras. We assessed NK‐cell tolerance in rat → mouse mixed xenogeneic chimeras using in vivo 125 I‐5iodo‐2‐deoxyuridine assays. Additional rapid marrow rejection mechanisms resulted in a requirement for 10‐fold more rat than ß2 microglobulin knockout (ß2M −/− ) (MHC class I‐deficient) mouse BMC to achieve engraftment in NK‐cell‐depleted mice. Both 12‐week mixed xenogeneic chimeras and conditioned controls showed reduced resistance to engraftment of ß2M −/− mouse and rat BMC. While conditioned control mice recovered NK‐cell‐mediated resistance to ß2M −/− and rat BMC by 16 weeks, mixed chimeras lacked resistance to either, similar to NK‐cell‐deficient Ly49A transgenic mice. Thus, global NK‐cell unresponsiveness is induced by mixed xenogeneic chimerism. Our data suggest that NK‐cell anergy is induced by interactions with xenogeneic hematopoietic cells that express activating but not inhibitory ligands for recipient NK cells.