Induction of myeloid-derived suppressor cells (MDSCs) by mycobacteria vaccines

• Applicant: Professor Dr. Manfred Lutz
• Subject Area: Immunology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442275424

Vaccination against tuberculosis (TB) is currently performed with Mycobacterium bovis Bacille-Calmette-Guérin (BCG). However, the protective effects are very limited. Vaccines based on the major human pathogen Mycobacterium tuberculosis (Mtb) or its antigens are still not available, despite enormous efforts. The reasons for this remain largely unknown. Since myeloid-derived suppressor cells (MDSCs) accumulate in patients with TB and in mice infected with live Mtb, it was possible that also killed Mtb vaccines may induce MDSCs and thereby impair vaccination success. Although Complete Freund's Adjuvant (CFA; containing heat-killed Mtb in oil) is a potent vaccine adjuvant, also immunosuppressive effects have been reported, that remain unexplained. Our published data indicated that monocytes can undergo a licensing process in vitro, which allowed their further conversion into Nos2-dependent NO releasing monocytic MDSCs (M-MDSCs). Our recently published data now indicate that the functional generation of CD11b+ Ly-6Chigh CD115+ iNOS+ M-MDSCs can be observed in vivo after Mtb vaccination, although their monocyte origin is unclear. These M-MDSC infiltrate the splenic bridging channels and white pulp where their NO production results in killing of dendritic cells (DCs), but unexpectedly not T cells. Collectively, these data reveal that Mtb booster vaccines induce M-MDSCs that kill DCs. However, several open questions remain to be addressed to better understand this phenomenon that may have impact also for clinical studies on Mtb vaccination.The objectives of this proposal are: 1) Demonstrate the conversion of monocytes into L-Mono and M-MDSC by different mycobacterial strains and compare live and dead vaccination protocols by fate mapping in vivo, 2) Demonstrate the detrimental role of live and dead vaccine-induced M-MDSCs for subsequent BCG and Mtb infections and the benefit of M-MDSC depletion during vaccination, 3) Unravel the role of the mTOR pathway specifically for M-MDSC function during mycobacterial vaccination and infection, 4) Dissect M-MDSC suppressor mechanisms of DC killing and T cell functional suppression or exhaustion after mycobacterial vaccination.

• DFG Programme: Research Grants