Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3–negative (FoxP3−), but not FoxP3+, CD4+T cells. Most IL-10–producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between “inflammaging” and impaired immune responses with age.

Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

The results obtained indicate a significant role of local cytokine production impairment in the development of adenomyosis.

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8+ T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10–13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8+ T cell responses were influenced to various extents by individual IFNα subtypes. IFNα4, 6, and 9 had the strongest effects on CD8+ T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFNα subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8+ T cells or DCs. Thus, precise modulation of virus-specific CD8+ T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFNα subtypes.