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.
Chen, P., Aguilar, O. A., Rahim, M. M. A., Allan, D. S. J., Fine, J., Kirkham, C. L., ... Carlyle, J. R. (2015). Genetic investigation of MHC-independent missing-self recognition by mouse NK cells using an in vivo bone marrow transplantation model
. Journal of Immunology
(6), 2909 - 2918. https://doi.org/10.4049/jimmunol.1401523