This difference in the breadth of the responses in individual mice may be a reflection of the differential degree of exhaustion of T cell subsets and/or differences in the precursor frequency in individual mice. synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction Regorafenib monohydrate in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer. Introduction CD8 T cells play a key role in eliminating and intracellular infections and tumors. However, in the setting of chronic antigen stimulation, such as that seen in chronic infections and tumors, CD8 T cells undergo exhaustion, causing them to become dysfunctional. This exhaustion is characterized by decreased proliferative capacity, loss of cytokine secretion, reduced cytotoxic killing abilities, and phenotypic changes, including low expression of canonical memory markers, such as the IL-7 receptor chain (CD127), and also an increase in inhibitory receptors (1C3). While multiple mechanisms contribute to the process of exhaustion, the inhibitory receptor programmed cell death 1 (PD-1) has emerged as a major player in this process. PD-1 is the most well-characterized inhibitory molecule upregulated during chronic antigen stimulation and is associated with disease progression and immune dysfunction (2). Importantly, recent data from 2 clinical trials have highlighted the role of PD-1 inhibition in human cancers and have shown that PD-1 blockade, by in vivo administration of humanized antiCPD-1 or antiCPD-1 ligand 1 (antiCPD-L1) antibodies, is an effective immunotherapeutic for increasing tumor clearance. Notably, in vivo PD-1 blockade resulted in durable tumor reduction or clearance in multiple cancers, including lung cancer, which is highly refractory to any treatment (4C6). These data correspond well with previous in vitro and in vivo animal model data showing that PD-1 plays a central role in T cell dysfunction during chronic infections and cancer and that PD-1 blockade can restore T cell function (2, 3, 7C16). Overall, these data indicate that PD-1 may be an important immunotherapeutic for cancers and chronic infections and signify that it is vital to find ways to increase the efficacy of PD-1 blockade. Multiple inhibitory mechanisms regulate CD8 T cell exhaustion, and, thus, combining PD-1 blockade along with other therapies, such as simultaneous blockade of multiple inhibitory receptors or therapeutic vaccination, results in enhanced reduction of viral loads and increased CD8 T cell responses in animal models of chronic infection. However, it is important to note that the mechanisms underlying the synergy of Regorafenib monohydrate combined Regorafenib monohydrate treatments has not been well explored (17C19). Overall, this suggests that combining strategies or treatments to combat chronic infections and cancer may be a valid strategy to increase efficacy. IL-2 is a cytokine that has a pleiotropic effect on multiple immune cell types and has been used as a therapy for several human diseases/conditions. IL-2 has been used to augment T cell responses against virus or tumor antigens in HIV and patients with metastatic cancer. While high-dose intermittent IL-2 therapy has increased long-term survival for some patients with metastatic renal cell carcinoma (20) and IL-2 therapy alone or in combination with a peptide vaccine has resulted in clinical improvement for patients with metastatic melanoma (21, 22), it has shown very limited success when given during chronic human viral infections, such as when it is combined Regorafenib monohydrate with antiretroviral drugs during HIV (23C28). Greater improvement was seen in one trial, with IL-2 administration combined with antiretroviral drugs and therapeutic vaccination during HIV infection (29), although other small studies suggest that a long-term effect is not seen after antiviral therapy is discontinued (30C32). However, continuous IL-2 administration, along with therapeutic vaccination and antiretroviral treatment, in macaques infected with chronic SIV increases SIV-specific CD8 T cell responses and results in decreased viral burden (33, 34). Overall, a major limitation of high-dose Regorafenib monohydrate intermittent IL-2 therapy is that it can result in severe toxicity issues, such as vascular leakage. By comparison, daily, much lower doses of IL-2 can ameliorate these toxicity issues (35). CD24 Recently promising human data indicate that daily low-dose IL-2 therapy may be useful for increasing Treg numbers and reducing autoimmune complications.