MDSC depletion during immunization with heat-killed Mycobacterium tuberculosis increases protection against BCG infection

Tuberculosis (TB) is still one of the deadliest infectious diseases globally. Although i.d. BCG immunization offers limited protection, a vaccine based on Mycobacterium tuberculosis (Mtb) has yet to be approved. Our previous findings demonstrated that s.c. immunization with heat-killed Mtb significantly increased the number of monocytic myeloid-derived suppressor cells (M-MDSC) in mice. Therefore, we hypothesized that the defense against a subsequent BCG infection would be impaired in Mtb-immunized mice. Surprisingly, mice vaccinated with Mtb were protected against a BCG infection and showed elevated frequencies and activation of DC and mycobacteria-specific T cells despite high frequencies and suppressor activity of M-MDSC. Genetic ablation of CCR2 ⁺ monocytic cells or pharmacological intervention with all-trans retinoic acid (ATRA) reduced the frequency of Mtb-induced M-MDSC, enhanced frequencies, and activation of dendritic cells (DC) and CD4 ⁺ T cells, and resulted in decreased bacterial loads in the lung and spleen. These findings offer fresh perspectives on TB vaccination using heat-killed Mtb despite parallel unwanted vaccine-induced M-MDSC. M-MDSC depletion by ATRA further tips the balance towards immunity and should be considered an adjunct host-directed therapy with TB vaccines in humans.