Irgm1 Restrains CD8 + T Cell Cytokine Production and Apoptosis via Cell‐Extrinsic Regulation of Type I Interferon Signaling
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| Natura: | Artículo Open Access |
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Wiley
2026
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| author | Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver |
| author_facet | Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver |
| collection | Wiley Open Access |
| contents | Irgm1 Restrains CD8 + T Cell Cytokine Production and Apoptosis via Cell‐Extrinsic Regulation of Type I Interferon Signaling Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver European Journal of Immunology ABSTRACT Immunity‐related GTPases (IRGs) are a family of proteins that maintain cellular homeostasis by promoting autophagy and mitophagy. Mutations in human IRGM and genetic deletion of mouse Irgm1 have been linked to increased severity of inflammatory bowel disease, cancer, sepsis, and various infections. While IRGM/Irgm1 are known cell‐intrinsic regulators of inflammation, their roles in T cell function remain poorly understood. We previously demonstrated that Irgm1 deficiency leads to increased production of proinflammatory mediators, including Granzyme B and interferon‐γ, and increased apoptosis in CD8 + T cells. Here, we show that Irgm1 deficiency also alters Granzyme B production and impairs virus‐specific CD8 + T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Using T cell‐specific Irgm1 knockout mice and adoptive transfer experiments, we unexpectedly found that Irgm1 regulates CD8 + T cell responses through a cell‐extrinsic mechanism. Transcriptomic and genetic analyses identified type I interferons (IFNs) as key mediators of this effect. These findings reveal a previously unrecognized, cell‐extrinsic role for Irgm1 in regulating CD8 + T cell survival and function by modulating the inflammatory environment. Our results suggest that IRGM/Irgm1 acts as a critical immune rheostat, restraining pathological inflammation and modulating T cell responses in infection and autoimmunity. 10.1002/eji.70113 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/eji.70113 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_eji_70113 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Irgm1 Restrains CD8 + T Cell Cytokine Production and Apoptosis via Cell‐Extrinsic Regulation of Type I Interferon Signaling Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver European Journal of Immunology Irgm1 Restrains CD8 + T Cell Cytokine Production and Apoptosis via Cell‐Extrinsic Regulation of Type I Interferon Signaling Caitlyn T. Molloy Yazan Alwarawrah Jonathan A. Cohen Brian E. Fee Jason K. Whitmire Gregory A. Taylor Nancie J. MacIver European Journal of Immunology ABSTRACT Immunity‐related GTPases (IRGs) are a family of proteins that maintain cellular homeostasis by promoting autophagy and mitophagy. Mutations in human IRGM and genetic deletion of mouse Irgm1 have been linked to increased severity of inflammatory bowel disease, cancer, sepsis, and various infections. While IRGM/Irgm1 are known cell‐intrinsic regulators of inflammation, their roles in T cell function remain poorly understood. We previously demonstrated that Irgm1 deficiency leads to increased production of proinflammatory mediators, including Granzyme B and interferon‐γ, and increased apoptosis in CD8 + T cells. Here, we show that Irgm1 deficiency also alters Granzyme B production and impairs virus‐specific CD8 + T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Using T cell‐specific Irgm1 knockout mice and adoptive transfer experiments, we unexpectedly found that Irgm1 regulates CD8 + T cell responses through a cell‐extrinsic mechanism. Transcriptomic and genetic analyses identified type I interferons (IFNs) as key mediators of this effect. These findings reveal a previously unrecognized, cell‐extrinsic role for Irgm1 in regulating CD8 + T cell survival and function by modulating the inflammatory environment. Our results suggest that IRGM/Irgm1 acts as a critical immune rheostat, restraining pathological inflammation and modulating T cell responses in infection and autoimmunity. 10.1002/eji.70113 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Irgm1 Restrains CD8 + T Cell Cytokine Production and Apoptosis via Cell‐Extrinsic Regulation of Type I Interferon Signaling |
| topic | European Journal of Immunology |
| url | https://onlinelibrary.wiley.com/doi/10.1002/eji.70113 |