Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.

Activated antigen-specific T cells produce a variety of effector molecules for clearing infection, but also contribute significantly to inflammation and tissue injury. Here we report an anti-inflammatory property of anti-viral CD8+ and CD4+ effector T cells (Te) in the infected periphery during acute virus infection. We find that, during acute influenza infection, IL-10 is produced in the infected lungs at high levels -- exclusively by infiltrating virus-specific Te, with CD8+ Te contributing a larger fraction of the IL-10 produced. These Te in the periphery simultaneously produce IL-10 and proinflammatory cytokines, and express lineage markers characteristic of conventional Th/c1 cells. Importantly, blocking the action of the Te-derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results demonstrate that anti-viral Te exert regulatory functions -- that is, fine-tune the extent of lung inflammation and injury associated with influenza infection by the production of an anti-inflammatory cytokine. The potential implications of these findings for infection with highly pathogenic influenza viruses are discussed.

Regulatory T cells (T reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b + myeloid cells in recombination-activating gene 1-deficient (Rag1 −/− ) recipient mice was needed to prevent the colitis induced by transferred CD4 + CD45RB hi T cells. In Il10 −/− Rag1 −/− mice, T reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb −/− ) T reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T reg cells to maintain Foxp3 expression. CD4 + regulatory T cells (T reg cells) express the transcription factor Foxp3 (A002750), which is required for their suppressive function. A T cell-transfer model of colitis has been widely used to study the function of T reg cells in vivo. When CD4 + CD45RB hi T cells are transferred into immunodeficient mice, some of the transferred T cells secrete proinflammatory cytokines and induce an inflammatory bowel disease-like syndrome 1,2 . Cotransfer of sufficient numbers of T reg cells can prevent or even cure this disease 3,4 . The transferred T reg cell populations expand considerably in vivo, and most maintain Foxp3 expression 5,6 .Mice deficient in interleukin 10 (IL-10 (A001243); Il10 −/− mice) or the IL-10 receptor β-chain (IL-10Rβ (A001245); Il10rb −/− mice) develop spontaneous inflammation of the large intestine, a process dominated by a T helper type 1 immune response7 ,8 . Many cell types can produce IL-10, however, and therefore the IL-10 source(s) needed to prevent inflammation must be identified. Much emphasis has been placed on the role of IL-10 released by CD4 + T cells, and in fact mice with conditional deletion of IL-10 in the CD4 + subset develop spontaneous inflammation of the intestine 9 . Mice with deletion of IL-10 solely in Foxp3 + cells also develop inflammation in the intestine and elsewhere, although the pathogenesis is less intense than that in mice completely lacking . Transgenic mice that overexpress IL-10 in intestinal epithelial cells are protected from colitis11, which suggests that IL-10 from nonlymphoid sources can be beneficial, although altered expression in the transgenic mice may not be physiologically relevant. NIH Public AccessTo further elucidate the cellular and molecular basis of the function of IL-10 in regulating colitis, we used the T cell-transfer model described above. We found that IL-10 from nonlymphoid cells, particularly CD11b + CD11c + cells, had an unexpectedly important influence on the development of colitis. Furthermore, we provide evidence that this IL-10 acted in part on T reg cells to maintain their expression of Foxp3, which was otherwise lost in inflammatory condit...