MTORCl-activated Monocytes Increase Tregs And Inhibit The Immune Response To Bacterial Infections

Background/Aims:Tuberous sclerosis complex(TSC) is encoded by Tsc1 or Tsc2 genes. The TSC1/2 heterodimer, a key upstream regulator of the mammalian target of rapamycin(mTOR) pathway, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. Method:In our study, mice with a homozygous deletion of Tsc1 in myeloid cells(Tsc1 KO) and wild type(WT) mice were infected with E. coli. We used E. coli infection modle, cellular co-culture experiments, RT-PCR, flow cytometry to explore the relationship between mTORC1-activated monocytes and the immune response to bacterial infections. Result:When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of co-activators(CD40, CD86, MHC-II, and CD14) in monocytes, increased numbers of regulatory T cells(Tregs) and decreased numbers of lymph node-resident effector T cells in Tsc1 KO mice. Monocytes obtained from Tsc1 KO mice produced more reactive oxygen species(ROS), IL-6, IL-10, and TGF-? and less pro-inflammatory cytokines(IL-1, IFN-?, and TNF-?). Conclusion:Taken together, our results suggest that the inhibited immune functioning in Tsc1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of co-activators resulted in inhibited effector T cell proliferation. In addition, the change in cytokine expression(IL-6, TGF-?, and IL-10), CD40 expression induced greater numbers of Tregs than in WT mice. mTORC1-activated monocytes are harmful during bacterial infections by inducing Tregs and inhibiting immune responses. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.