Published online before print May 19, 2009

This Article Full Text Free Full Text (PDF) Free Supplemental Figures 1 & 2 All Versions of this Article: jlb.1208740v1 86/3/713    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Windish, H. P. Articles by Flynn, J. L. Search for Related Content PubMed PubMed Citation Articles by Windish, H. P. Articles by Flynn, J. L.

(Journal of Leukocyte Biology. 2009;86:713-725.)
© 2009 Society for Leukocyte Biology

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

Hillarie Plessner Windish^*,1, P. Ling Lin, Joshua T. Mattila^*, Angela M. Green^*, Ezenwa Obi Onuoha, Lawrence P. Kane and JoAnne L. Flynn^*,2

^* Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA;
Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA;
Department of Natural Science, Virginia Union University, Richmond, Virginia, USA; and
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

2. Correspondence: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, W1157 Biomedical Science Tower, Pittsburgh, PA 15261, USA. E-mail: joanne{at}pitt.edu

ABSTRACT

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.

Key Words: tuberculosis • granuloma • ICAM-1 • Foxp3 • Treg

This article has been cited by other articles:

				P. L. Lin and J. L. Flynn Understanding Latent Tuberculosis: A Moving Target J. Immunol., July 1, 2010; 185(1): 15 - 22. [Abstract] [Full Text] [PDF]