Natural killer cells in inflammatory autoimmune diseases

Abstract

Natural killer (NK) cells are a specialised population of innate lymphoid cells (ILCs) that help control local immune responses. Through natural cytotoxicity, production of cytokines and chemokines, and migratory capacity, NK cells play a vital immunoregulatory role in the initiation and chronicity of inflammatory and autoimmune responses. Our understanding of their functional differences and contributions in disease settings is evolving owing to new genetic and functional murine proof-of-concept studies. Here, we summarise current understanding of NK cells in several classic autoimmune disorders, particularly in rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM), but also less understood diseases such as idiopathic inflammatory myopathies (IIMs). A better understanding of how NK cells contribute to these autoimmune disorders may pave the way for NK cell-targeted therapeutics.

Keywords: autoimmune disease; idiopathic inflammatory myopathies; multiple sclerosis; natural killer cells; rheumatoid arthritis; systemic lupus erythematosus; type 1 diabetes mellitus.

Figure 1

NK cell involvement in autoimmune inflammatory diseases. NK cells exacerbate RA by secreting soluble mediators such as (a) M‐CSF and RANKL that drive the differentiation of bone‐eroding osteoclasts and (b) GM‐CSF that promotes the production of pro‐inflammatory mediators by joint‐infiltrating neutrophils. (c) NK cells do not appear to play a dominant role in MS but boosting their cytotoxic function with anti‐NKG2A may eliminate encephalitogenic Th17 cells and alleviate disease in the EAE model. (d) NK cells may promote SLE through their interaction with pDCs via LFA‐1 and DNAM‐1 that enhances the production of cytokines and chemokines such as IFN‐α, IFN‐γ, TNF‐α, IL‐6, IL‐8, CCL3 and CCL4. NK cells are also found in kidney of lupus nephritis patients but it remains unclear if NK cells and their cytokine dysfunction contribute to tissue pathology. (e) NK cells could contribute to the generation of autoantigens through excessive killing of CV‐B4‐infected pancreatic β islets. However, other functions of NK cells such as IFN‐γ production remain unclear and future studies are required to capture phenotypic and functional diversity of NK cells in both CV‐B4‐associated and sterile T1DM subtypes. (f) Alveolar NK cells are thought to give rise to autoantigens such as histidyl tRNA synthetase following respiratory insults in anti‐synthetase syndrome. Future studies are needed to evaluate whether similar numerical and functional changes in NK cells occur in the discrete subtype of IIM.

Figure 2

Therapeutic potential of NK‐based therapy in autoimmune disorders. (a) Blocking or agonistic antibodies target cell‐surface receptors of NK cells to potentiate their cytotoxicity against autoreactive immune cells, or suppress the production of pathogenic cytokines. (b) Engineering of chimeric antigen receptor (CAR) could direct NK cells to eliminate autoreactive immune cells. (c) A multifunctional engager combining antibodies that target antigens expressed by autoreactive cells and activating/inhibitory receptors on NK cells could facilitate NK cell interaction and cytolytic activity towards target autoimmune lymphocytes.