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The lung is the primary site of infection with the major human pathogen, Mycobacterium tuberculosis. Effective vaccines against M. tuberculosis must stimulate memory T cells to provide early protection in the lung. Recently, tissue-resident memory T cells (T) were found to be phenotypically and transcriptional distinct from circulating memory T cells. Here, we identified M. tuberculosis-specific CD4 T cells induced by recombinant influenza A viruses (rIAV) vaccines expressing M. tuberculosis peptides that persisted in the lung parenchyma with the phenotypic and transcriptional characteristics of T. To determine if these rIAV-induced CD4 T were protective independent of circulating memory T cells, mice previously immunized with the rIAV vaccine were treated with the sphingosine-1-phosphate receptor modulator, FTY720, prior to and during the first 17 days of M. tuberculosis challenge. This markedly reduced circulating T cells, but had no effect on the frequency of M. tuberculosis-specific CD4 T in the lung parenchyma or their cytokine response to infection. Importantly, mice immunized with the rIAV vaccine were protected against M. tuberculosis infection even when circulating T cells were profoundly depleted by the treatment. Therefore, pulmonary immunization with the rIAV vaccine stimulates lung-resident CD4 memory T cells that are associated with early protection against tuberculosis infection.

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...