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.
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Aberrant TGF-β signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis
Windish, Hillarie Plessner; Lin, P. Ling; Mattila, Joshua T.; Green, Angela M.; Onuoha, Ezenwa Obi; Kane, Lawrence P.; Flynn, JoAnne L.
Follow Journal of Leukocyte Biology
, Volume 86 (3): 713
Fed of American Socs for Experimental Biology – Sep 1, 2009
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