Bacillus Calmette-Guérin-induced interleukin-10 inhibits S100A8/A9 production and hinders development of T helper type 1 memory in mice.

Tuberculosis caused by Mycobacterium tuberculosis (M.tb) is one of the main causes of human death in the world. Bacillus Calmette-Guérin (BCG) provides limited protection in adolescents and adults. To explore the factors reducing efficacy of BCG vaccine, we assess the impacts of interleukin (IL)-10 and alarmins S100A8/A9 on T-cell memory. We found that BCG-induced IL-10 inhibited production of S100A8/A9 in human peripheral blood mononuclear cells (PBMCs) and murine splenocytes. S100A9 deficiency inhibited IFN-γ production by CD4+ T cells in the early phase of BCG immunization and hindered the development of effector memory T helper type 1 (Th1) cells, while IL-10 deficiency promoted Th1 memory and blocking IL-10 signaling enhanced Th1 protective recall response against M.tb. IL-10 inhibited the binding of transcription factor CCAAT enhancer binding protein beta to S100a8/a9 promoter leading to S100A8/A9 reduction. S100A8/A9 heterodimer enhanced the IFN-γ production via receptor for advanced glycation end products signaling in CD4+ T cells. Our results demonstrate a hurdle to development of Th1 memory after BCG immunization and clarify the mechanism of the regulation of Th1 memory by IL-10 and S100A8/A9.

Absence of PD-L1 signaling hinders macrophage defense against Mycobacterium tuberculosis via upregulating STAT3/IL-6 pathway.

The blockade of programmed death-ligand 1 (PD-L1) pathway has been clinically used in cancer immunotherapy, while its effects on infectious diseases remain elusive. Roles of PD-L1 signaling in the macrophage-mediated innate immune defense against M.tb is unclear. In this study, the outcomes of tuberculosis (TB) in wild-type (WT) mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1ΔΜΦ) mice were compared. Treatment with anti-PD-L1 or anti-PD-1 benefited protection against M.tb infection in WT mice, while Pdl1ΔΜΦ mice exhibited the increased susceptibility to M.tb infection. Mechanistically, the absence of PD-L1 signaling impaired M.tb killing by macrophages. Furthermore, elevated STAT3 activation was found in PD-L1-deficient macrophages, leading to increased interleukin (IL)-6 production and reduced inducible nitric oxide synthase (iNOS) expression. Inhibiting STAT3 phosphorylation partially impeded the increase in IL-6 production and restored iNOS expression in these PD-L1-deficient cells. These findings provide valuable insights into the complexity and mechanisms underlying anti-PD-L1 therapy in the context of tuberculosis.