The roles of NK cells in the pathogenesis of Sjögren's syndrome

Abstract

Natural killer (NK) cells are an important component of the innate immune system which play important roles in the responses against viruses and tumors. They can also regulate immune responses via suppressing other immune cells or secreting cytokines. Sjögren’s syndrome (SS) is an autoimmune disease characterized by the inflammation in the lacrimal glands and the salivary glands (SG), causing dry eyes and dry mouth. The adaptive immune responses are critically involved in the pathogenesis of SS. B cells secrete autoantibodies, while T cells secrete various cytokines to promote immune responses and cause tissue damages. Innate immune cells such as plasmacytoid dendritic cells, monocytes and macrophages also play a role via secreting interferons or presenting autoantigens. However, the roles of NK cells in SS are less well-defined. This study aimed to elucidate the roles of NK cells in the development of SS, with the help of the experimental SS (ESS) mouse model, which recaptured various aspects of human SS. First, NK cells in the SG (SG NK cells) were characterized. NK cells account for approximately half of total SG leukocytes in the naïve mice, suggesting their importance in SG immunity. At least part of the SG NK cells are derived from the bone marrow, but their turnover is slow at the normal state. An SG-specific CD49a+CD103hi NK cell population is observed. They express high levels of ectoenzymes which convert ATP, ADP, AMP and NAD+ into the immunosuppressive molecule adenosine. SG NK cells can suppress the proliferation of CD4+ T cells in vitro, which is reversed by inhibition of the ectoenzyme CD73, suggesting adenosine mediates the suppressive effects of SG NK cells. The phenotype of SG NK cells is maintained by the microenvironment of SG, in which TGF- possibly plays an important role. Next, the dynamic, the phenotypic and functional changes of NK cells in ESS mouse model were analyzed. SG NK cells are decreased during ESS, with increased apoptosis and decreased proliferation. Their expression of CD73 is also downregulated, which possibly contributes to the attenuation of suppressive effects on CD4+ T cells. On the other hand, their potential target cells in the SG downregulate the adenosine A2a receptor during ESS, which may render them less responsive to adenosine. Finally, the effects of SG NK cells in ESS were investigated via local depletion. Depletion of SG NK cells exacerbated dry mouth and leukocyte infiltration in the SG. In the SG of SG NK-depleted mice, IFN- was upregulated in CD4+ T cells and CD8+ T cells, while IL-17A was upregulated in CD4+ T cells and T cells, suggesting SG NK cells suppress Th1 and Th17 responses in the development of ESS. In this study, SG NK cells are revealed to be phenotypically and functionally different from peripheral NK cells, and they regulate T cell responses in the SG during ESS in a CD73-dependent manner. Reversing the decrease of SG NK cells or potentiating their regulatory effects may serve as effective therapeutic approaches against SS. (491 words)