Circulating NK cells establish tissue-residency upon acute infection of skin and mediate accelerated effector responses to secondary infection

Natural killer (NK) cells are present in the circulation and can also be found residing in tissues; these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigated whether circulating conventional NK (cNK) cells can develop into long-lived, tissue-resident cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi tissue-resident (trNK) cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK arose from IFN-?-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissueresidency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny. Overall design: Group 1 ILCs from spleen, blood and skin were sorted from naive or VACV acutely infected or rechallenged mice. List of Hashtags and Cite seq antibodies used in this study: Hashtag2_TotalA GGTCGAGAGCATTCA, Hashtag3_TotalA CTTGCCGCATGTCAT, Hashtag4_TotalA AAAGCATTCTTCACG, Hashtag5_TotalA CTTTGTCTTTGTGAG, Hashtag6_TotalA TATGCTGCCACGGTA. CD45_TotalA TGGCTATGGAGCAGA, CD45.1_TotalA CCTATGGACTTGGAC, CD45.2_TotalA CACCGTCATTCAACC, CD11b_TotalA TGAAGGCTCATTTGT, CD25_TotalA ACCATGAGACACAGT, CD27_TotalA CAAGGTATGTCACTG, CD49a_TotalA CCATTCATTTGTGGC, CD49b_TotalA CGCGTTAGTAGAGTC, CD62L_TotalA TGGGCCTAAGTCATC, CD69_TotalA TTGTATTCCGCCATT, CD127_TotalA GTGTGAGGCACTCTT, CD160_TotalA GCGTATGTCAGTACC, CD200r_TotalA ATTCTTTCCCTCTGT, CX3CR1_TotalA CACTCTCAGTCCTAT, Cxcr6_TotalA TGTCAGGTTGTATTC, KLRG1_TotalA GTAGTAGGCTAGACC, NK1.1_TotalA GTAACATTACTCGTC, NKp46_TotalA CCCTTTCACCTCGAA. We multiplexed mem rechall skin with Hashtag_2, mem ctrl skin with Hashtag_3, naïve chall skin with Hashtag_4, naïve ctrl spleen with Hashtag_5, and naïve ctrl blood with Hashtag_6.