CTLs can produce the regulatory cytokine IL-10 to prevent excess inflammation during clearance of viruses. Braciale and colleagues now unravel the molecular pathways involved in IL-10 expression by CTLs. Interleukin (IL)-10 is an important regulatory cytokine that can modulate excessive immune mediated injury. Several distinct cell types have been demonstrated to produce IL-10, including most recently CD8+ cytotoxic T lymphocytes (CTLs) responding to respiratory virus infection. Here we report that CD4+ T cell help in the form of IL-2 is required for IL-10 production by CTLs, but not for the induction of CTL effector cytokines. We show that IL-2 derived from CD4+ helper T cells cooperates with innate immune cell–derived IL-27 to amplify IL-10 production by CTLs through a Blimp-1-dependent mechanism. These findings reveal a previously unrecognized pathway that coordinates signals derived from innate and helper T cells to control the production of a regulatory cytokine by CTLs during acute viral infection.

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A_2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A_2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A_2AR agonists. In addition, administration of DCs treated ex vivo with an A_2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A_2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A_2AR–induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI.

Influenza A virus (IAV) infection in the respiratory tract triggers robust innate and adaptive immune responses, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of ongoing inflammation and tissue repair occur during a distinct recovery period. B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV infection, but their potential role during recovery and resolution of inflammation is unknown. We found that antibody-mediated CD86 blockade in vivo after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in airways and lung interstitium, but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3⁺ regulatory T cells (Tregs), and adoptive transfer of Tregs into αCD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Specific depletion of Tregs late after infection mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Furthermore, we identified neutrophils as a target of Treg suppression since neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that Tregs, in a CD86 dependent mechanism, contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways. Influenza A virus (IAV) infection can cause severe inflammation and injury in the respiratory tract, which must be resolved and repaired for the host to fully recover after virus clearance. Evidence is emerging that host immune responses may regulate tissue repair and resolution of inflammation after IAV infection. Early in IAV infection, the co-stimulatory molecules CD80 and CD86 promote inflammation through triggering IAV-specific T cell responses, but no role for CD80/86 in recovery after virus clearance has been previously established. By in vivo antibody-mediated blockade of CD80 or CD86 after virus clearance, we found that engagement of CD86 (but not CD80) was required for optimal recovery after influenza infection. Furthermore, we determined that CD86 was essential for maintaining the FoxP3⁺regulatory T cell (Treg) population in the respiratory tract, and CD86-dependent Tregs promoted recovery by suppressing pulmonary inflammation and supporting regain of weight after virus clearance. In addition, we demonstrated that Tregs suppress neutrophils late after infection, preventing neutrophils from driving excess inflammatory cytokine release into the airways. Taken together, we propose a novel role for CD86 engagement late after IAV infection to promote resolution of inflammation and host recovery through a Treg-dependent mechanism.

Foxp3⁺T regulatory (T_reg) cells suppress immune cell activation and establish normal immune homeostasis. How T_regcells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for T_regcell stability and function.Ndfip1deletion in T_regcells results in autoinflammatory disease. Ndfip1-deficient T_regcells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing T_H2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient T_regcells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts T_regcell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient T_regcells. Thus, Ndfip1 preserves T_reglineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active T_regcells and by preventing pathological secretion of IL-4 from T_regcells.