Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions.

Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4 + and CD8 + T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4 + T-cell epitope from the Ag85B protein (PR8.p25) or CD8 + T-cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T-cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4 + T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8 + T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4 + , but not CD8 + T cells, is essential for protection against acute M. tuberculosis infection in the lung. Keywords: CD4 + T cells r Interferon-γ r Lung r Recombinant influenza A virus r TuberculosisAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTuberculosis (TB) is still one of the major causes of death worldwide, and it is estimated that one-third of the world's population Correspondence: Dr. Manuela Flórido e-mail: m.florido@centenary.org.au is infected by Mycobacterium tuberculosis (M. tuberculosis; WHO 2012, http://www.who.int/tb/publications/global_report). The only vaccine currently used, BCG, although effective at protecting young children, fails to protect adults from the pulmonary form of the disease with efficacies that range from 0 to 80% [1]. The most advanced vaccine in human studies is MVA85A, a nonreplicative vaccinia viral vector expressing M. tuberculosis Ag85A, but the results of a phase II clinical trial showed no additional C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 780-793 Immunity to infection 781 protective effect of this vaccine over BCG against clinical TB or the acquisition of M. tuberculosis infection in infants [2]. The development of more effective vaccines is therefore essential. The immune response against primary infection with M. tuberculosis in a naïve host involves mostly CD4 + T cells so unsurprisingly anti-TB vaccines were initially designed to induce a strong CD4 + T-cell response. That was the case for BCG and subunit vaccines that are potent inducers of systemic anti-M. tuberculosis CD4 + T-cell responses [3]. Emerging evidence that CD8 + T cells also played a role in both the immune response to M. tuberculosis infection and in the vaccin...

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