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

目前，针对结核病（TB）的疫苗接种是用牛分枝杆菌卡介苗（BCG）进行的。但是，保护作用非常有限。尽管作出了巨大努力，但仍然没有基于主要人类病原体结核分枝杆菌（Mtb）或其抗原的疫苗。其原因在很大程度上仍不清楚。由于髓源性抑制细胞（MDSC）在TB患者和感染活Mtb的小鼠中积累，因此灭活Mtb疫苗也可能诱导MDSC，从而损害疫苗接种成功。尽管完全弗氏佐剂（CFA;在油中含有热灭活的Mtb）是一种有效的疫苗佐剂，但也报道了免疫抑制作用，其仍然无法解释。我们发表的数据表明，单核细胞可以在体外经历许可过程，这允许它们进一步转化为Nos 2依赖性NO释放单核MDSC（M-MDSC）。我们最近发表的数据现在表明，在Mtb疫苗接种后，可以在体内观察到CD 11b + Ly-6Chigh CD 115 + iNOS+ M-MDSC的功能性产生，尽管它们的单核细胞来源尚不清楚。这些M-MDSC浸润脾桥接通道和白色髓，其中它们的NO产生导致树突状细胞（DC）的杀伤，但出乎意料地不是T细胞。总的来说，这些数据揭示了Mtb加强疫苗诱导杀死DC的M-MDSC。然而，为了更好地理解这一现象，仍有几个悬而未决的问题有待解决，这一现象也可能对结核分枝杆菌疫苗接种的临床研究产生影响。1）证明单核细胞通过不同分枝杆菌菌株转化为L-Mono和M-MDSC，并通过体内命运作图比较活的和死的疫苗接种方案，2）证明活的和死的疫苗诱导的M-MDSC对于随后的BCG和Mtb感染的有害作用以及疫苗接种期间M-MDSC消耗的益处，4）剖析分枝杆菌疫苗接种后DC杀伤和T细胞功能抑制或衰竭的M-MDSC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.