Natural Killer Cells in Kidney Health and Disease

Abstract

Natural killer (NK) cells are a specialized population of innate lymphocytes that have a major effector function in local immune responses. While their immunological functions in many inflammatory diseases are well established, comparatively little is still known about their roles in kidney homeostasis and disease. Our understanding of kidney NK cells is rapidly evolving, with murine studies highlighting the functional significance of NK cells in acute and chronic forms of renal disease. Recent progress has been made in translating these murine findings to human kidneys, with indications of NK cell subset-specific roles in disease progression in both native and allograft kidneys. Clearly, a better understanding of the molecular mechanisms driving NK cell activation and importantly, their downstream interactions with intrinsic renal cells and infiltrating immune cells is necessary for the development of targeted therapeutics to halt disease progression. In this review, we discuss the properties and potential functions of kidney NK cells.

Keywords: acute kidney injury; chronic kidney disease; glomerulonephritis; natural killer cells; transplantation.

Figure 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 injury, NK cells can engage in direct interaction with activating molecules expressed on 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.

Figure 2

Potential function of NK cells in chronic kidney disease. In human kidney fibrosis, NK cells reside in the tubulointerstitium and express the NK cell receptor NKp46 that can recognize stressed cells. In addition, the NKG2D ligand MICA is upregulated in tubular epithelial cell (TECs) of patients with lupus nephritis. In settings of chronic inflammation, NK cells could exert direct cytotoxic effects on damaged tubular epithelial cells. Moreover, kidney NK cells have been shown to produce IFN-γ in human CKD which could induce proinflammatory mediators in renal parenchymal cells and promote “classical” M1 activation of macrophages, both resulting in progression of renal inflammation.

Figure 3

Proposed function of NK cells in human antibody-mediated renal allograft rejection. In antibody-mediated rejection, donor-specific antibodies (DSA) bind to allograft endothelial cells. The interaction of these antibodies with the Fc receptor CD16 that is highly expressed on the CD56^dim NK cell subset could trigger antibody-dependent cell-mediated cytotoxicity directed against endothelial cells, resulting in microvascular injury of the kidney allograft.