Type I IFN signaling in the absence of IRGM1 promotesM. tuberculosisreplication in immune cells by suppressing T cell responses

Abstract

Polymorphisms in theIRGMgene are associated with susceptibility to tuberculosis in humans. A murine ortholog ofIrgm,Irgm1, is also essential for controllingMycobacterium tuberculosis(Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infectionin vivoand the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesisin vivoand found thatIrgm1deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion inIrgm1-/-mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses.

CCR8 antagonist suppresses liver cancer progression via turning tumor-infiltrating Tregs into less immunosuppressive phenotype

“…Neutrophils act as the body's rst line of defense against infection and respond to diverse in ammatory cues, including cancer. Although the role of IRGM1 in neutrophils in cancer scenarios remains to be investigated, based on the recent study that the IRGM1 is required to promote T cell-mediated control of infection in neutrophils [40], and on our results that IRGM1 + neutrophils express high levels of CXCL2, CXCL10, and CXCR2, chemokines and receptors involved in neutrophil recruitment and T cell activation, we reasonably postulate that the IRGM1 + neutrophils promote anticancer immunity. Though it is largely unknown how CCR8 blockade with UIPG0521m resulted in increased in ltration of IRGM1 + neutrophils, a study with an in ammatory disease model indicated that CCR8 de ciency reduced eosinophil accumulation but accelerated neutrophil accumulation in the in ammatory site, suggesting that CCR8 blockade may promote neutrophil accumulation [41].…”