Project B15 – Deciphering cell fate decisions of single NK cells during infection
We recently found that clonal expansion of individual NK cells, harboring the same activating receptor, Ly49H, specific to the m157 protein encoded by murine cytomegalovirus (MCMV), varied massively in response to infection. This expansion was related to ‘avidity selection’ of Ly49Hhi expressing NK cell clones upon MCMV infection. We will now determine the relevance of competition with other NK cell activating receptors (NKAR) for shaping the NKAR repertoire and for enabling infection-driven ‘avidity selection’ of NK cell clones. Based on the observation that cells from NK cell clones can adopt two phenotypically distinct response patterns upon MCMV infection, i.e. as conventional NK (cNK) cells or as a hitherto unrecognized subset of spleen-resident NK (srNK) cells, we will expore a critical innate-to-adaptive bridging function for the latter. Finally, we will determine the long-term capacity of single cNK and srNK cells for maintenance of memory-like immune responses. Together, this project will provide novel insight into the regulation of the NK cell receptor repertoire, the role of specific NK cell subsets and the putative stem cell-like basis for adaptive-like NK cell immunity, and holds the potential of informing novel strategies for therapeutic enhancement of NK cell function.
