| Summary: | Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i>, results in approximately 1.6 million deaths annually. BCG is the only TB vaccine currently in use and offers only variable protection; however, the development of more effective vaccines is hindered by a lack of defined correlates of protection (CoP) against <i>M. tuberculosis</i>. Pulmonary vaccine delivery is a promising strategy since it may promote lung-resident immune memory that can respond rapidly to respiratory infection. In this study, CysVac2, a subunit protein previously shown to be protective against <i>M. tuberculosis</i> in mouse models, was combined with either Advax<sup>®</sup> adjuvant or a mixture of alum plus MPLA and administered intratracheally into mice. Peripheral immune responses were tracked longitudinally, and lung-local immune responses were measured after challenge. Both readouts were then correlated with protection after <i>M. tuberculosis</i> infection. Although considered essential for the control of mycobacteria, induction of IFN-γ-expressing CD4<sup>+</sup> T cells in the blood or lungs did not correlate with protection. Instead, CD4<sup>+</sup> T cells in the lungs expressing IL-17A correlated with reduced bacterial burden. This study identified pulmonary IL-17A-expressing CD4<sup>+</sup> T cells as a CoP against <i>M. tuberculosis</i> and suggests that mucosal immune profiles should be explored for novel CoP.
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