Tissue-Resident NK Cells Mediate Ischemic Kidney Injury and Are Not Depleted by Anti–Asialo-GM1 Antibody

Abstract

NK cells are innate lymphoid cells important for immune surveillance, identifying and responding to stress, infection, and/or transformation. While conventional NK (cNK) cells circulate systemically, many NK cells reside in tissues where they appear to be poised to locally regulate tissue function. Here we tested the contribution of tissue-resident NK (trNK) cells to tissue homeostasis by studying ischemic injury in the mouse kidney. Parabiosis experiments demonstrate that the kidney contains a significant fraction of trNK cells under homeostatic conditions. Kidney trNK cells developed independent of NFIL3 and Tbet, and expressed a distinct cell surface phenotype as compared to cNK cells. Among these, trNK cells had reduced asialo-GM1 (AsGM1) expression relative to cNK cells, a phenotype observed in trNK cells across multiple organs and mouse strains. Strikingly, anti-AsGM1 antibody treatment, commonly used as NK cell-depleting regimen, resulted in a robust and selective depletion of cNKs, leaving trNKs largely intact. Using this differential depletion, we tested the relative contribution of cNK and trNK cells in ischemic kidney injury. Whereas anti-NK1.1 antibody effectively depleted both trNK and cNK cells and protected against ischemic-reperfusion injury, anti-AsGM1 antibody preferentially depleted cNK cells and failed to protect against injury. These data demonstrate unanticipated specificity of anti-AsGM1 antibody depletion on NK cell subsets and reveal a new approach to study the contributions of cNK and trNK cells in vivo. In total, these data demonstrate that trNK cells play a key role in modulating local responses to ischemic tissue injury in the kidney and potentially other organs.

Osteopontin Blockade Attenuates Renal Injury After Ischemia Reperfusion by Inhibiting NK Cell Infiltration

“…NK cells have previously been shown to be important for RIR injury (9–11). NK cells produce toxic molecules such as perforin and granzymes that induce cell death (12).…”

“…Innate immune cells such as natural killer (NK) cells, neutrophils, and macrophages become activated and migrate to the tissue, which causes further cellular injury of the TECs through the release of cytokines and reactive oxygen species (7, 8). Of the innate immune cells, NK cells are cytotoxic lymphocytes which play a critical role in RIR injury (9–11). These cells contain perforin and granzymes, and upon release in proximity to target cells, perforin forms pores in the cell membrane through which granzymes can enter, causing apoptosis or osmotic cell lysis (12).…”

NFIL3 Expression Distinguishes Tissue-Resident NK Cells and Conventional NK-like Cells in the Mouse Submandibular Glands

“…Thymic NK cells represent another population that develops from unique precursors, and are Ly49 low CD11b low and CD127 + CD69 high , in contrast to cNK cells (4, 5). A unique population of trNK cells has also recently been discovered in the kidneys (6). The current understanding is that cNK cells, together with liver and skin trNK (ILC1), uterine NK cells, thymic NK cells, and kidney trNK cells, account for multiple distinct NK cell lineages (3, 7).…”

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

“…One study found that antiasialo GM1 does not deplete tissue-resident NK cells in the kidney. 53 But within that same article, the authors have shown that uterine tissue-resident NK cells seem to be an exception because they were uniformly expressing high levels of asialo GM1 that was similar to circulating NK cells in some strains. 53 Currently, the only way of temporarily depleting or reducing NK cells in the rat is administering antibodies or the antiserum anti-asialo GM1.…”