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Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis(Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovisBacille Calmette‐Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub‐optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen‐specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1(BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1‐infected DCs were more effective at driving the production of IFN‐γ and IL‐17 from antigen‐specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1‐infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen‐specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1‐infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG‐infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge.

ABSTRACTMycobacterium tuberculosissuccessfully subverts the host immune response to promote disease progression. In addition to its known intracellular niche in macrophages, M. tuberculosisinterferes with the functions of dendritic cells (DCs), which are the primary antigen-presenting cells of the immune system. We previously showed that M. tuberculosisdampens proinflammatory responses and impairs DC functions through the cell envelope-associated serine protease Hip1. Here we present data showing that M. tuberculosisGroEL2, a substrate of Hip1, modulates DC functions. The full-length GroEL2 protein elicited robust proinflammatory responses from DCs and promoted DC maturation and antigen presentation to T cells. In contrast, the cleaved form of GroEL2, which predominates in M. tuberculosis, was poorly immunostimulatory and was unable to promote DC maturation and antigen presentation. Moreover, DCs exposed to full-length, but not cleaved, GroEL2 induced strong antigen-specific gamma interferon (IFN-γ), interleukin-2 (IL-2), and IL-17A cytokine responses from CD4+T cells. Moreover, the expression of cleaved GroEL2 in the hip1mutant restored the robust T cell responses to wild-type levels, suggesting that proteolytic cleavage of GroEL2 allows M. tuberculosisto prevent optimal DC-T cell cross talk during M. tuberculosisinfection.