STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells.

Adaptive immune responses to Ags released by dying cells play a critical role in the development of autoimmunity, allograft rejection, and spontaneous as well as therapy-induced tumor rejection. Although cell death in these situations is considered sterile, various reports have implicated type I IFNs as drivers of the ensuing adaptive immune response to cell-associated Ags. However, the mechanisms that underpin this type I IFN production are poorly defined. In this article, we show that dendritic cells (DCs) can uptake and sense nuclear DNA-associated entities released by dying cells to induce type I IFN. Remarkably, this molecular pathway requires STING, but not TLR or NLR function, and results in the activation of IRF3 in a TBK1-dependent manner. DCs are shown to depend on STING function in vivo to efficiently prime IFN-dependent CD8(+) T cell responses to tumor Ags. Furthermore, loss of STING activity in DCs impairs the generation of follicular Th cells and plasma cells, as well as anti-nuclear Abs, in an inducible model of systemic lupus erythematosus. These findings suggest that the STING pathway could be manipulated to enable the rational design of immunotherapies that enhance or diminish antitumor and autoimmune responses, respectively.

Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice.

Tumor cell vaccination with irradiated autologous tumor cells is a promising approach to activate tumor-specific T cell responses without the need for tumor Ag identification. However, uptake of dying cells by dendritic cells (DCs) is generally a noninflammatory or tolerizing event to prevent the development of autoreactive immune responses. In this study, we describe the mechanisms that confer the potent T cell priming capacity of a recently identified a population of DCs (merocytic DCs [mcDCs]) that potently primes both CD8(+) and CD4(+) T cells to cell-associated Ags upon uptake of apoptotic cells. mcDCs acquired cell-associated materials through a process of merocytosis that is defined by the uptake of small particles that are stored in nonacidic compartments for prolonged periods, sustained Ag presentation, and the induction of type I IFN. T cells primed by mcDCs to cell-associated Ags exhibit increased primary expansion, enhanced effector function, and increased memory formation. By using transgenic T cell transfer models and endogenous models, we show that treatment of tumor-bearing mice with mcDCs that have been exposed to dying tumor cells results in tumor suppression and increased host survival through the activation of naive tumor-specific CD8(+) T cells as well as the reinvigoration of tumor-specific T cells that had been rendered nonresponsive by the tumor in vivo. The potent capacity of mcDCs to prime both CD4(+) and CD8(+) T cells to cell-associated Ags under immunosuppressive conditions makes this DC subset an attractive target for tumor therapies as well as interventional strategies for autoimmunity and transplantation.

Distinct roles of cytolytic effector molecules for antigen-restricted killing by CTL in vivo.

Cytotoxic T lymphocytes (CTLs) represent one of the front lines of defense for the immune system, killing virus-infected and tumor-transformed cells. CTL use at least two mechanisms to induce apoptosis in their targets, one mediated by perforin and granzymes, and the other triggered by the death ligand, CD95 ligand (CD95L). Here, we used an in vivo cytotoxicity assay to measure specific clearance of antigen-bearing target cells in mice that had previously been immunized with noninfectious cell-associated antigens. We found that perforin was dispensable for efficient clearance of antigen-bearing cells from immunized mice, but only if CD95/CD95L was functional; however, there was a delay in target cell clearance in the absence of perforin. In addition, we observed ∼35% target cell clearance in the absence of both perforin and CD95L, which was only slightly abrogated in the presence of a neutralizing anti-tumor necrosis factor (TNF) antibody. The presence of a dominant negative Fas-associated death domain (FADD) did not block target cell clearance and therefore cannot be attributed to known death receptors. Taken together, these data suggest that perforin- and CD95L-dependent killing are complementary at early time points, each can compensate for the absence of the other at later time points, and that there is an additional component of antigen-restricted CTL killing independent of perforin, CD95L, and TNFα.