Indeed, we have presented evidence that NK cells in the kidney are a heterogeneous population of innate lymphocytes with subset-specific functional roles. is usually transiently recruited to the kidney. In humans, the expression of CD69 (a C-lectin receptor) has been used to discriminate tissue-resident from circulating lymphocytes (21C23). Our group recently reported the expression of CD69 on human NK cells (predominantly on CD56bright NK cells) in healthy kidney tissue (20). Based on this initial indication of tissue residency, we speculate that human NK cells in healthy kidneys serve as sentinels to maintain barrier integrity and protect against pathogens, as has been suggested for tissue-resident NK cells in other human peripheral organs (7, 24C26). The concept of a specialized NK cell subset that resides in the kidney tissue and is characterized by minimal exchange with its recirculating counterparts is usually supported by a recent study in mice. Using a parabiosis approach, a technique in which the blood circulations of two animals are surgically anastomosed, investigators showed that this murine kidney harbors two distinct populations of NK cells: tissue-resident (tr) NK cells with the surface marker combination Acitazanolast CD49a+CD49b?, representing ~20% of the total NK cell pool in the kidney, and conventional (c) NK cells which are CD49a?CD49b+ (16). The kidney-residing trNK cells displayed a surface marker profile distinct from cNK cells, did not require the cNK cell transcription factor NFIL3 for their development, partially depended on T-bet expression and, most importantly, were of functional relevance in a mouse model of ischemic AKI (see below) (16). However, whether these trNK cells Acitazanolast play a role in maintaining kidney homeostasis in the steady-state or serve as a first line of defense against invading pathogens remains to be elucidated. NK Cells in Ischemic AKI AKI is usually a clinical condition defined by acute impairment of kidney function, caused by heterogeneous etiologies including ischemia, sepsis and toxic insults. The most common morphology of (severe) AKI is usually acute tubular necrosis (ATN). Immunohistological examinations of NK cells in human ATN are limited because clinical practice is not to biopsy when the impairment is usually expected to be time limited (27). Despite this, there is evidence that NK cells do indeed participate in AKI due to ATN Mouse monoclonal to CD47.DC46 reacts with CD47 ( gp42 ), a 45-55 kDa molecule, expressed on broad tissue and cells including hemopoietic cells, epithelial, endothelial cells and other tissue cells. CD47 antigen function on adhesion molecule and thrombospondin receptor in humans. Highlighting their potential pathogenic function, NK cells have been shown to directly kill human tubular epithelial cells (TECs) exposed to hypoxic conditions mimicking ischemic AKI (28). This cytotoxic function was dependent on the direct conversation of activating NKG2D receptor on NK cells and its ligand MICA expressed on TECs. In mice, the kidney ischemia/reperfusion model has been used in several studies to investigate the role of NK cells in the induction and regeneration of ischemic ATN (29). It was further shown that ischemic injury of TECs upregulates their expression of Rae-1 and other stress molecules, such as the costimulatory molecule CD137L (30). Conversation of CD137L on TECs with CD137+ NK cells resulted in the induction of CXCL2 expression in TECs, leading to neutrophil recruitment and immune-mediated progression of tubular damage (Physique 1) (30). Open in a separate window Physique 1 Function of NK cells in the ischemia/reperfusion mouse model of AKI. (A) After ischemic injury, tubular epithelial cells (TECs) release endogenous damage-associated molecular pattern (DAMPs) that activate surrounding TECs via TLR2 to express CCR5 ligands, mediating NK cell recruitment. In addition, production of osteopontin (OPN) by injured TECs activates NK cells and indirectly regulates their recruitment, by a yet unknown mechanism. (B) After recruitment to the areas of ischemic Acitazanolast injury, NK cells can engage in direct conversation with activating molecules expressed around the damaged epithelium. Activation of NK cells by these ligand: receptor interactions, such as NKG2D on NK cells and Rae-1 on TECs, results in perforin-dependent TEC killing. Interaction of CD137L on TECs with CD137+ NK cells results in the induction of CXCL2 expression in TECs, leading to neutrophil recruitment and immune-mediated progression of tubular damage. TECs are also instrumental in the initial recruitment of NK cells to the kidney in ischemic injury. By expressing molecules that induce NK cell chemotaxis, such.