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Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy.

Alveolar macrophages (AMs) from mice and humans have long been known to contribute to maintaining tolerance in the lung. Studies have shown that AMs can induce anergy in CD4(+) T cells. Nitric oxide, prostaglandins, and leukotrienes have been implicated in AM-mediated tolerance. However, it remains unclear what effect, if any, AMs exert on FoxP3 induction in CD4(+) T cells from mice and humans, and whether or not other immunomodulators might play a role. AMs were isolated from bronchoalveolar lavage (BAL) fluid from either mice or humans, and cocultured with enriched naive CD4(+)FoxP3(-) T cells. We show here for the first time that AMs and AM-conditioned media (AM-CM) from mice and humans induced FoxP3 expression in naive CD4(+) T cells in vitro, an outcome that was reversed in part either by inhibiting retinoic acid (RA) binding to its receptor (RAR), or by blocking transforming growth factor (TGF)-β₁ signaling. A nasal administration of the RAR antagonist reduced the frequencies of CD4(+)FoxP3(+) T cells in the lungs of mice after aerosol challenge with Bordetella pertussis. In addition, we found that the intranasal vaccination of mice with ovalbumin (OVA) protein in conjunction with an RAR inhibitor led to a significant increase in OVA-specific serum IgE. Our findings suggest that AMs can mediate tolerance in the lungs of mice and humans via RA and TGF-β₁. These data may have implications in the development of nasal vaccines in the future.