Genetic investigation of MHC-independent missing-self recognition by mouse NK cells using an in vivo bone marrow transplantation model

Peter Chen, Oscar A Aguilar, Mir M A Rahim, David S J Allan, Jason Fine, Christina L Kirkham, Jaehun Ma, Miho Tanaka, Megan Tu, Andrew Wight, Vicky Kartsogiannis, Matthew T Gillespie, Andrew P Makrigiannis, James R Carlyle

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15 Citations (Scopus)

Abstract

MHC-I-specific receptors play a vital role in NK cell-mediated missing-self recognition, which contributes to NK cell activation. In contrast, MHC-independent NK recognition mechanisms are less well characterized. In this study, we investigated the role of NKR-P1B:Clr-b (Klrb1:Clec2d) interactions in determining the outcome of murine hematopoietic cell transplantation in vivo. Using a competitive transplant assay, we show that Clr-b-/- bone marrow (BM) cells were selectively rejected by wild-type B6 recipients, to a similar extent as H-2Db-/- MHC-I-deficient BM cells. Selective rejection of Clr-b-/- BM cells was mitigated by NK depletion of recipient mice. Competitive rejection of Clr-b-/- BM cells also occurred in allogeneic transplant recipients, where it was reversed by selective depletion of NKR-P1Bhi NK cells, leaving the remaining NKR-P1Blo NK subset and MHC-I-dependent missing-self recognition intact. Moreover, competitive rejection of Clr-b-/- hematopoietic cells was abrogated in Nkrp1b-deficient recipients, which lack the receptor for Clr-b. Of interest, similar to MHC-I-deficient NK cells, Clr-b-/- NK cells were hyporesponsive to both NK1.1 (NKR-P1C)-stimulated and IL-12/18 cytokine-primed IFN-gamma production. These findings support a unique and nonredundant role for NKR-P1B:Clr-b interactions in missing-self recognition of normal hematopoietic cells and suggest that optimal BM transplant success relies on MHC-independent tolerance mechanisms. These findings provide a model for human NKR-P1A:LLT1 (KLRB1:CLEC2D) interactions in human hematopoietic cell transplants.
Original languageEnglish
Pages (from-to)2909 - 2918
Number of pages10
JournalJournal of Immunology
Volume194
Issue number6
DOIs
Publication statusPublished - 2015

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