Mouse natural killer subsets defined by their target specificity and their ability to be separately rendered unresponsive in vivo.

Abstract

NK cells from F1(AxB) hybrid mice are known to reject bone marrow grafts from either parent A or parent B (hybrid resistance). Using cold target competition in an in vitro hybrid resistance assay, we demonstrate in this work that parent A and parent B are killed by different NK subsets. As confirmation of the existence of these subsets, and to determine whether they undergo a selection/education process during NK cell ontogeny, we constructed bone marrow chimeras in which NK1.1-depleted bone marrow cells from F1 mice were allowed to mature in the microenvironment of either parent A or parent B. These F1-reconstituted chimeras were shown to have normal NK cell numbers and lytic ability in terms of YAC-1 killing and Ab-mediated redirected lysis. Using a three-color flow cytometry analysis in an in vivo hybrid resistance assay, we found that A targets, but not B targets, were less effectively removed by the F1 NK cells that develop in an A recipient (F1-->A chimeras) than in normal F1 or F1-->F1 chimeric mice. IL-2-activated killer cultures of cells from these chimeras, however, did not show a significant difference in the anti-parent killing response in an in vitro assay. These results suggest that NK cells exist in subsets and that self-reactive NK subsets can be rendered unresponsive by radioresistant host element(s). However, this unresponsiveness can be broken when the NK cells are removed from the in vivo environment.