Under conditions of high antigenic load during infection with invasive lymphocytic choriomeningitis virus (LCMV) strains, virus can persist by selective clonal exhaustion of antigen-specific CD8؉ T cells. In this work we studied the down-regulation of the virus-specific CD8؉ -T-cell response during a persistent infection of adult mice, with particular emphasis on the contribution of the interferon response in promoting host defense. Viruses use a number of strategies, including escape from immune recognition or induction of immunosuppression, to avoid immunological surveillance and thereby persist in the host (reviewed in references 1, 14, 35, 45, and 59). The immune response to viruses involves activation of both effector arms of the adaptive immune system, i.e., virus-specific CD8 ϩ T cells and neutralizing antibody production, as well as components of the innate response, including type I (alpha/beta interferon [IFN-␣/␤]) and type II (IFN-␥) IFNs (27,56,69,72). IFNs are an essential part of both the innate and adaptive cytokine responses to viral infection, having important functions in the regulation of the immune system (12,24,38,49). In addition to inducing an antiviral state (24, 38), IFNs are noted for their function in many immunoregulatory processes, including upregulation of major histocompatibility complex (MHC) class I and II molecules, activation of macrophages and natural killer cells (68), augmentation of dendritic cell responses, and promotion of proliferation and survival of activated lymphocytes (15,36,60).Infection of mice with the relatively noncytopathic lymphocytic choriomeningitis virus (LCMV) results in an early and dramatic elevation of IFN-␣/␤, within day 2 to 3 of infection (18, 67). The adaptive T-cell immune response, characterized by profound CD8 ϩ -T-cell expansion and IFN-␥ production, is elicited by day 7 to 9 after infection (11,23,73). The central concept derived from studies with this viral system is that in previously unexposed individuals a race occurs between the development of cell-mediated immunity and the extent of viral replication. Virus clearance or persistence is determined by a critical balance between the virus-specific immune response and the rate of virus replication. Consistent with this model, virus control and functional T-cell memory, or viral persistence and exhaustion of virus-specific CD8 ϩ T cells, reflect the ends of the spectrum of the virus-host interaction. Thus, infection with invasive strains of LCMV that can rapidly replicate and produce a high viral load can drive the activation and vigorous expansion of antigen-specific CD8 ϩ T cells, followed by their functional inactivation resulting in irreversible anergy and/or deletion (43,71). This phenomenon, called clonal exhaustion, results in viral persistence. In contrast, infection with less invasive, slowly replicating LCMV strains induces virus-specific T cells capable of efficiently clearing the infection. Typically, a fraction of these cells persist as long-term memory cells after virus eliminati...

Cytosolic DNA sensing is an important process during the innate immune response that activates the Stimulator of Interferon Genes (STING) adaptor and induce interferon type I (IFN-I). STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). While STING also induced IDO in tumor-draining lymph nodes (TDLNs) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8+ T cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL-10 production in the TME. Depletion of CD8+ T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8+ T cell effector functions during tumorigenesis. In contrast to native LLC tumors, STING signaling did not promote growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity, and how IDO inhibition can overcome this state by attenuating tumor tolerance. Further, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials.

SUMMARY At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells, without loss of the transcription factor Foxp3. We show that reprogramming is controlled by down-regulation of the transcription factor Eos (Ikzf4), an obligate co-repressor for Foxp3. Reprogramming was restricted to a specific subset of “Eoslabile” Treg cells which were present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Down-regulation of Eos required the pro-inflammatory cytokine IL-6, and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos, and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells.

Tumors depend on a specialized pathway of regulatory T cell activation to create their immunosuppressive microenvironment, which can be blocked by inhibiting PTEN phosphatase.