IFN-γ: A cytokine at the right time, is in the right place.

Interferon gamma has long been studied as a critical mediator of tumor immunity. In recent years, the complexity of cellular interactions that take place in the tumor microenvironment has become better appreciated in the context of immunotherapy. While checkpoint inhibitors have dramatically improved remission rates in cancer treatment, IFN-γ and related effectors continue to be identified as strong predictors of treatment success. In this review, we provide an overview of the multiple immunosuppressive barriers that IFN-γ has to overcome to eliminate tumors, and potential avenues for modulating the immune response in favor of tumor rejection.

The chemokine CCL5 regulates glucose uptake and AMP kinase signaling in activated T cells to facilitate chemotaxis.

Recruitment of effector T cells to sites of infection or inflammation is essential for an effective adaptive immune response. The chemokine CCL5 (RANTES) activates its cognate receptor, CCR5, to initiate cellular functions, including chemotaxis. In earlier studies, we reported that CCL5-induced CCR5 signaling activates the mTOR/4E-BP1 pathway to directly modulate mRNA translation. Specifically, CCL5-mediated mTOR activation contributes to T cell chemotaxis by initiating the synthesis of chemotaxis-related proteins. Up-regulation of chemotaxis-related proteins may prime T cells for efficient migration. It is now clear that mTOR is also a central regulator of nutrient sensing and glycolysis. Herein we describe a role for CCL5-mediated glucose uptake and ATP accumulation to meet the energy demands of chemotaxis in activated T cells. We provide evidence that CCL5 is able to induce glucose uptake in an mTOR-dependent manner. CCL5 treatment of ex vivo activated human CD3(+) T cells also induced the activation of the nutrient-sensing kinase AMPK and downstream substrates ACC-1, PFKFB-2, and GSK-3ß. Using 2-deoxy-d-glucose, an inhibitor of glucose uptake, and compound C, an inhibitor of AMPK, experimental data are presented that demonstrate that CCL5-mediated T cell chemotaxis is dependent on glucose, as these inhibitors inhibit CCL5-mediated chemotaxis in a dose-dependent manner. Altogether, these findings suggest that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5. These studies extend the role of CCL5 mediated CCR5 signaling beyond lymphocyte chemotaxis and demonstrate a role for chemokines in promoting glucose uptake and ATP production to match energy demands of migration.

Antiviral effects of interferon-ß are enhanced in the absence of the translational suppressor 4E-BP1 in myocarditis induced by Coxsackievirus B3.

BACKGROUND: Viral myocarditis is most frequently associated with infection by Coxsackievirus B3 (CVB3). Interferon (IFN)-ß therapy has been studied and could reduce virally induced tissue damage and improve heart function. METHODS: In the present study we have investigated the role of translational suppression in the context of an IFN-α/ß-mediated antiviral immune response to CVB3 infection. Specifically, we examined the effects of IFN-α/ß treatment of CVB3-infected mouse embryonic fibroblast cells and splenocytes lacking eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a suppressor of 5'-capped mRNA translation. Extending these in vitro studies, we examined the effects of CVB3 infection and IFN-ß treatment in 4E-BP1(-/-) mice. RESULTS: Our data show that 4E-BP1(-/-) cells are more -sensitive to the antiviral effects of IFN-α4 and IFN-ß treatment than 4E-BP1(+/+) cells when infected with CVB3. Similarly, 4E-BP1(-/-) mice are more sensitive to treatment with IFN-ß, exhibiting lower viral titres in heart tissue than 4E-BP1(+/+) mice during the course of infection. Additionally, we demonstrate that treatment with IFN-ß reduces inflammatory infiltrates into the hearts of infected mice. CONCLUSIONS: These data identify 4E-BP1 as a novel drug target to augment responsiveness to IFN-ß therapy in CVB3-induced myocarditis.