Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses

Jul 22, 2024Mucosal immunology

Type I interferon signaling without IRGM1 helps tuberculosis bacteria grow in immune cells by weakening T cell responses

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Abstract

Irgm1 deletion results in uncontrolled Mycobacterium tuberculosis infection in mice.

Polymorphisms in the IRGM gene may increase tuberculosis susceptibility in humans.
The Irgm1 gene in mice is crucial for controlling Mtb infection.
Deletion of Irgm1 leads to elevated levels of type I interferon signaling.
Increased type I interferon signaling may inhibit T cell expansion during Mtb infection.
Without Mtb-specific T cell expansion, there is uncontrolled Mtb infection in neutrophils and macrophages.
IRGM1 is essential for T cell-mediated control of Mtb infection, impacting survival in infected mice.

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Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium 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 infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion 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 in Irgm1mice 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 T1 immune responses. -/-H

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