Immunoregulatory Natural Killer Cells Suppress Autoimmunity by Down-Regulating Antigen-Specific CD8+ T Cells in Mice

Abstract

Natural killer (NK) cells belong to the innate immune system. Besides their role in antitumor immunity, NK cells also regulate the activity of other cells of the immune system, including dendritic cells, macrophages, and T cells, and may, therefore, be involved in autoimmune processes. The aim of the present study was to clarify the role of NK cells within this context. Using two mouse models for type 1 diabetes mellitus, a new subset of NK cells with regulatory function was identified. These cells were generated from conventional NK cells by incubation with IL-18 and are characterized by the expression of the surface markers CD117 (also known as c-Kit, stem cell factor receptor) and programmed death (PD)-ligand 1. In vitro analyses demonstrated a direct lysis activity of IL-18-stimulated NK cells against activated insulin-specific CD8(+) T cells in a PD-1/PD-ligand 1-dependent manner. Flow cytometry analyses revealed a large increase of splenic and lymphatic NK1.1(+)/c-Kit(+) NK cells in nonobese diabetic mice at 8 wk of age, the time point of acceleration of adaptive cytotoxic immunity. Adoptive transfer of unstimulated and IL-18-stimulated NK cells into streptozotocin-treated mice led to a delayed diabetes development and partial disease prevention in the group treated with IL-18-stimulated NK cells. Consistent with these data, mild diabetes was associated with increased numbers of NK1.1(+)/c-Kit(+) NK cells within the islets. Our results demonstrate a direct link between innate and adaptive immunity in autoimmunity with newly identified immunoregulatory NK cells displaying a potential role as immunosuppressors.

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

“…Evidence supporting a regulatory role for NK cells in diverse immunopathological conditions such as viral infections, autoimmunity, and transplantation is emerging (12)(13)(14)(15)(16)(17). However, little is known about a possible regulatory activity during an antitumor immune response.…”

“…PD-L1 expression on c-Kit + CD11b 2 NK cells during experimental diabetes (17) and metastatic spread of cancer (51) has been reported. However, in our experimental setting, we observed that PD-L1 + NK cells showed no detectable expression of c-Kit and were mostly terminally differentiated, expressing high levels of CD11b.…”

“…Although it has been widely demonstrated in various model systems that NK cells can play a positive role during immune responses against tumors and infected cells, evidence of an inhibitory role for NK cells is beginning to emerge in diverse models of viral infection (12)(13)(14)(15), transplantation (16), and autoimmunity (17). It has been reported that NK cells regulate T cell responses through multiple direct and indirect mechanisms, including NK cell-mediated killing of activated CD8 + T cells (14,15,(18)(19)(20)(21), CD4 + T cells (18,19,22,23), and also of dendritic cells (DCs) (12,24,25).…”

Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection

“…More recently, it was shown that the cytokine induces PDL-1 on NK cells, and the PDL-1 + NK cells could provide protection from CTL-mediated autoimmunity. Paradoxically, the cells could also promote immunosuppression and promote cancer progression [48]. The IL-18-induced PDL-1 + immunoablative NK cells were shown to be Kit + CD11b À that arose from Kit À CD11b À precursor cells.…”

NK cells in immunotolerant organs

“…24 high NK cells producing the largest number of cytokines and having the strongest cytotoxicity. 24 Interestingly, a new subset of NK cells with a regulatory function was identified in a study by Ehlers et al 31 using two mouse models for type 1 diabetes mellitus; this new immunoregulatory NK cell subset, characterized by the surface markers CD117 (also known as c-Kit) and programmed death-ligand 1, suppresses autoimmunity by downregulating antigen-specific CD8…”