Infection induces tissue-resident memory NK cells that safeguard tissue health.

Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases. [Display omitted] • NK cells are recruited and retained in non-lymphoid tissues after CMV infection • NK cells form a long-lived, tissue-resident, memory-like population: NKRM cells • NKRM regulation of CD4+ T cell responses in the SG requires TRAIL • NKRM cells prevent immune-mediated damage and safeguard optimal tissue function Immune activation can be damaging if responses are not adequately controlled. Schuster et al. reveal that following cytomegalovirus infection, circulating natural killer cells are recruited into non-lymphoid tissues, including the salivary glands, where they establish a tissue-resident, memory-like population that prevents immune-mediated damage and safeguards tissue health by preventing autoimmunity. [ABSTRACT FROM AUTHOR]