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

目前，结核病疫苗接种是使用牛分枝杆菌卡介苗(BCG)。然而，保护作用是非常有限的。尽管付出了巨大努力，基于人类主要病原体结核分枝杆菌(Mtb)或其抗原的疫苗仍然无法获得。造成这种情况的原因在很大程度上仍不清楚。由于髓系来源的抑制细胞(MDSCs)在结核病患者和感染活Mtb的小鼠体内积聚，因此也有可能也被灭活的Mtb疫苗诱导MDSCs，从而损害疫苗接种的成功。尽管完全弗氏佐剂(CFA；在油中含有热灭活的结核分枝杆菌)是一种有效的疫苗佐剂，但也有免疫抑制作用的报道，但原因尚不清楚。我们发表的数据表明，单核细胞在体外可以经历一个许可过程，这使得它们可以进一步转化为NOS2依赖的释放NO的单核细胞MDSCs(M-MDSCs)。我们最近发表的数据表明，在结核分枝杆菌疫苗接种后，可以在体内观察到CD11b+Ly-6 Chigh CD115+iNOS+M-MDSCs的功能生成，尽管其单核细胞来源尚不清楚。这些M-MDSC渗透到脾桥接通道和白髓，它们的NO产生导致树突状细胞(DC)的杀伤，但出乎意料的是T细胞不被杀死。总而言之，这些数据揭示了结核分枝杆菌强化疫苗诱导的M-MDSCs杀死DC。然而，为了更好地理解这一现象，也可能对结核分枝杆菌疫苗的临床研究产生影响，仍有几个有待解决的问题。本研究的目的是：1)展示不同分枝杆菌株将单核细胞转化为L-单核细胞和M-MDSC，并通过体内命运图谱比较活疫苗和死亡疫苗诱导的M-MDSC；2)证明活疫苗和死亡疫苗诱导的M-MDSC在随后的卡介苗和结核分枝杆菌感染中的不利作用以及M-MDSC在疫苗接种过程中的好处；3)揭示M-MDSC功能的mTOR通路在分枝杆菌疫苗接种和感染过程中的作用，4)分析分枝杆菌疫苗接种后M-MDSC对DC杀伤和T细胞功能抑制或耗竭的抑制机制。

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.