Natural killer (NK) cells are a type of white blood cell that play a major role in the innate immune system. They were first discovered in the 1970s for their ability to kill tumor cells without prior sensitization, hence the name “natural killer” cells. Since then, research has uncovered that NK cells have diverse functions beyond just killing. They are involved in immune regulation, pregnancy, and tissue remodeling. An important question is whether NK cells normally reside in the kidneys or are recruited there during inflammation and disease. In this article, we will examine the evidence on the presence and roles of NK cells in healthy and diseased kidneys.
Overview of Natural Killer Cells
NK cells originate from hematopoietic stem cells in the bone marrow. They circulate in the blood and lymphatic system, surveying for abnormalities. NK cells do not need prior exposure to activate their functions like adaptive immune cells do. Instead, they rely on a sophisticated set of activating and inhibitory receptors that detect stress signals and missing “self” markers on cells. Healthy cells express MHC class I molecules that engage inhibitory NK receptors, blocking NK activation. When cells are infected, transformed or stressed, they downregulate MHC class I and express altered molecules that bind to activating NK receptors. This triggers the NK cell to release cytotoxic granules and cytokines that eliminate the abnormal cell. Besides this key role in tumor immunosurveillance, NK cells regulate immunity by producing cytokines and interacting with other white blood cells like dendritic cells. They also exhibit memory-like responses after certain viral infections.
Presence of NK Cells in Healthy Kidneys
The kidneys filter blood to remove wastes and maintain fluid and electrolyte balance. This exposes the kidneys to pathogens and toxins that can cause injury. NK cells provide innate immune protection against kidney infections. But do they normally reside in the kidneys or only enter during inflammation? Understanding baseline NK biology in the kidneys is important for interpreting their roles in kidney diseases.
Research over the past decades provides evidence that NK cells are present in healthy kidneys in animals and humans:
Animal Studies
– In mice, NK cells make up 5-20% of lymphocytes in the kidney during normal health. They localize mostly in the renal medulla and cortex rather than the glomeruli.
– Rat kidneys also contain NK cells in similar proportions and locations as in mice.
– Canine kidneys harbor NK cells scattered throughout the interstitium of the cortical and juxtamedullary regions.
– Porcine NK cells have been found in the interstitium of healthy pig kidneys.
Human Studies
– Analyses of normal human kidney samples show CD56+ CD3- NK cells comprising around 5% of lymphocytes in the renal interstitium.
– NK cells isolated from healthy human kidneys display a surface marker profile typical of circulating NK cells.
– Single cell RNA sequencing has identified CD56+ NK cell transcripts in kidney samples from living donors.
In summary, animal and human studies provide consistent evidence that NK cells normally reside in low numbers in the interstitial areas of the kidneys. Their localization in strategic areas allows rapid innate responses against pathogens entering through the urinary tract.
Changes in NK Cells in Kidney Diseases
While NK cells protect the kidneys during health, their roles in kidney diseases are complex. The numbers and properties of renal NK cells change dynamically during different types of kidney inflammation and injury:
Acute Kidney Injury
– Ischemia-reperfusion injury: NK cell activation and cytotoxicity can worsen tubular damage after restoration of blood flow. Depletion of NK cells reduced kidney injury in rodent models.
– Cisplatin nephrotoxicity: NK cells infiltrate the kidneys and directly kill tubular cells via perforin/granzyme-dependent cytotoxicity. Their depletion or inhibition protected against cisplatin-induced AKI in mice.
– Sepsis: Septic AKI in mice showed increased infiltration and activation of NK cells along with augmented cytokine production and cytotoxicity. However, NK cell depletion did not improve sepsis-induced kidney dysfunction.
Glomerulonephritis
– Lupus nephritis: NK cells expand in the peripheral blood and kidneys of SLE patients. However, their role is complex with both protective and pathogenic effects reported.
– IgA nephropathy: Numbers of NK cells are elevated in kidneys of IgAN patients and correlate with disease severity. The NK cells show signs of activation and cytotoxicity.
– ANCA vasculitis: In ANCA-associated GN, increased circulating NK cells display an immature phenotype and reduced cytotoxicity. Kidney NK cells appear protective by limiting neutrophil infiltration.
Transplant Rejection
– Acute rejection: Higher NK cell infiltration is found in kidney allografts undergoing T cell-mediated rejection. Their role is unclear but they may modulate graft injury.
– Chronic rejection: Reduced NK cells are found in graft biopsies with chronic rejection. Their deficiency may impair anti-fibrotic activity.
In summary, diverse kidney disorders demonstrate dynamic alterations in renal NK cell numbers, phenotype, localization, and functions. Clarifying their complex, context-dependent roles in nephropathies requires more research.
Mechanisms of NK Cell Recruitment to Kidneys
The increased presence of NK cells in diseased kidneys implies active recruitment from the circulation. Chemokines play crucial roles in guiding NK cell migration. Studies find the following chemokines are involved in attracting NK cells to the kidneys:
CXCL9, CXCL10, CXCL11
These chemokines bind CXCR3 expressed on NK cells. Their production is upregulated in damaged kidneys, creating a chemokine gradient that draws CXCR3+ NK cells to the site of injury.
CX3CL1
Kidney epithelial cells express this chemokine which recruits NK cells by engaging their receptor CX3CR1. Mice deficient in CX3CR1 have fewer renal NK cells and better outcomes in models of ischemic and septic AKI.
CCL2, CCL5
These ligands for CCR5 attract NK cells in various kidney disorders. Mice lacking CCR5 or its ligands have reduced renal NK infiltration after AKI. Blocking CCR5/CCL5 interaction prevented maladaptive NK cell responses.
CXCL1
This neutrophil chemoattractant additionally recruits NK cells via CXCR2. Its blockade attenuated NK infiltration in mouse AKI models.
In summary, the chemokines CXCL9-11, CX3CL1, CCL2, CCL5, and CXCL1 have been implicated in NK cell recruitment during nephropathies. Targeting their pathways could potentially modulate damaging NK responses while preserving protective functions.
Functions of NK Cells in Kidney Disease
Renal NK cells exhibit diverse functional changes in different disease states. Their complex roles can be broadly categorized as:
Cytotoxicity
NK cells can directly kill stressed tubular cells and infiltrating leukocytes via:
– Perforin and granzyme release
– Death receptor-mediated apoptosis (FasL, TRAIL)
– Antibody-dependent cell-mediated cytotoxicity (ADCC)
Excess cytotoxicity worsens AKI and tubulointerstitial damage. NK cell depletion or inhibition of their cytotoxic pathways often attenuated kidney injury in animal models.
Cytokine Production
Activated NK cells secrete cytokines like IFN-γ, TNF-α, GM-CSF that amplify inflammation and immunopathology. However, they also produce regulatory cytokines like IL-10 that counterbalance inflammation. The balance depends on the kidney microenvironment.
Interaction with Other Immune Cells
NK cells bidirectionally interact with dendritic cells, macrophages, T cells and B cells during kidney inflammation via direct contact and cytokines. These interactions can either augment pathogenic immunity or promote regulatory responses.
Tissue Regeneration
There is evidence that NK cells can promote tissue repair in the kidneys by:
– Limiting neutrophil destruction
– Secreting pro-proliferative factors like HGF
– Polarizing macrophages to pro-healing phenotypes
In different contexts, NK cells can play both detrimental and beneficial roles in the kidneys through their cytotoxicity, cytokine production, immunomodulation, and regeneration functions. More research is needed to fully understand their complex contributions to nephropathies.
Conclusion
In conclusion, the current evidence indicates that:
– NK cells are normally present in low numbers in the interstitium of healthy kidneys in animals and humans.
– Renal NK cells undergo dynamic changes in localization, numbers, phenotype, and functions during diverse kidney disorders.
– Damaging effects of excessive NK cytotoxicity and inflammation have been demonstrated in many kidney disease models. However, NK cells also have regenerative and regulatory potential.
– Chemokines like CXCL9-11, CX3CL1, CCL2/5 are involved in recruiting circulating NK cells to injured kidneys.
– The ultimate roles of NK cells depend on the specific context such as disease type, stage, microenvironment. More research is needed to clarify their complex, context-dependent contributions.
– Targeting the right NK pathways to suppress detrimental effects while retaining protective functions may have therapeutic potential in kidney diseases.
In patients with kidney disorders, analysis of NK cells in blood versus kidney biopsies along with their phenotypic markers and functional properties can provide insights into their participation in disease pathogenesis versus resolution. A precision medicine approach tailored to the disease and individual may be needed to harness the full potential of NK cells for treatment of kidney diseases.