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mTOR signaling is a pivotal negative determinant of MDSC recruitments in immune‐mediated hepatic injury diseases. The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. MDSCs are a heterogeneous cell population that plays a crucial regulatory effect in immune‐related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11b+Gr1+MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11b+Gr1+Ly6ChighMDSC recruitment to inflammatory sites. In agreement with this, mTOR down‐regulation promotes CD11b+Gr1+Ly6ChighMDSC migration in vitro and in vivo. Mechanistically, mTOR activity down‐regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11b+Gr1+Ly6ChighMDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH‐related diseases.

A progressive decline in the integrity of the immune system is one of the physiologic changes during aging. The frequency of autoimmune diseases or immune disorders increases in the aging population, but the state of regulatory T (Treg) cells in aged individuals has not been well determined. In the present study, we investigated the levels, phenotypes, and function of CD4+CD25+Treg cells in Balb/c mice, which were older than 20 months. Significantly enhanced percentages of CD4+CD25+Treg cells in the periphery (blood, spleen, and lymph nodes) of the aged mice were observed. These Treg cells showed modified Vβ family distribution, reduced levels of CD45 receptor B and CD62 ligand molecules, as well as normal levels of forkhead box p3. However, when the inhibiting function of Treg cells was assayed in the in vitro assays and in a delayed‐type hypersensitivity (DTH) model, CD4+CD25+Treg cells of aged mice displayed significantly lower inhibiting ability on alloantigen‐induced DTH reaction or cytokine productions (IL‐2 and IFN‐γ) but not cell proliferation of effector T cells, as compared with CD4+CD25+Treg cells of young mice. In addition, the percentages of CD4+CD8–CD25+Treg cells in the thymi of aged mice increased significantly, but their total cell numbers decreased markedly in these mice. Our present studies indicated collectively that the percentages, phenotypes, the size of TCR repertoire, and function of CD4+CD25+Treg cells were altered significantly with aging in mice. The functional defects of CD4+CD25+Treg cells may shed light on the role of CD4+CD25+Treg cells in the increased sensitivity to autoimmune diseases of aged populations.