Aberrant TGF-β signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis

• Published in: Journal of leukocyte biology Vol. 86; no. 3; pp. 713 - 725
• Main Authors: Windish, Hillarie Plessner, Lin, P. Ling, Mattila, Joshua T., Green, Angela M., Onuoha, Ezenwa Obi, Kane, Lawrence P., Flynn, JoAnne L.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.09.2009; The Society for Leukocyte Biology
• Subjects: Animals; Foxp3; granuloma; Host Defense & Pathophysiology; ICAM‐1; Inflammation; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - immunology; Interferon-gamma - metabolism; Mice; Mice, Knockout; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - metabolism; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism; Treg; tuberculosis
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1208740

Uncontrolled lung pathology resulting from reduced T regulatory cells causes increased susceptibility to Mycobacterium tuberculosis in ICAM‐1‐deficient mice. Foxp3+ T regulatory cells are required to prevent autoimmune disease, but also prevent clearance of some chronic infections. While natural T regulatory cells are produced in the thymus, TGF‐β1 signaling combined with T‐cell receptor signaling induces the expression of Foxp3 in CD4+ T cells in the periphery. We found that ICAM‐1−/− mice have fewer T regulatory cells in the periphery than WT controls, due to a role for ICAM‐1 in induction of Foxp3 expression in response to TGF‐β1. Further investigation revealed a functional deficiency in the TGF‐β1‐induced translocation of phosphorylated Smad3 from the cytoplasmic compartment to the nucleus in ICAM‐1‐deficient mice. This impairment in the TGF‐β1 signaling pathway is most likely responsible for the decrease in T regulatory cell induction in the absence of ICAM‐1. We hypothesized that in the presence of an inflammatory response, reduced production of inducible T regulatory cells would be evident in ICAM‐1−/− mice. Indeed, following Mycobacterium tuberculosis infection, ICAM‐1−/− mice had a pronounced reduction in T regulatory cells in the lungs compared with control mice. Consequently, the effector T‐cell response and inflammation were greater in the lungs of ICAM‐1−/− mice, resulting in morbidity due to overwhelming pathology.