HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0804346v1 183/4/2484    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Tsantikos, E. Articles by Hibbs, M. L. PubMed PubMed Citation Articles by Tsantikos, E. Articles by Hibbs, M. L.

Perturbation of the CD4 T Cell Compartment and Expansion of Regulatory T Cells in Autoimmune-Prone Lyn-Deficient Mice¹

Evelyn Tsantikos^*,, Cathy Quilici^*, Kenneth W. Harder^2,*, Bo Wang, Hong-Jian Zhu, Gary P. Anderson, David M. Tarlinton and Margaret L. Hibbs^3,*

^* Signal Transduction Laboratory, Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, and Immunology Division, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia; and Department of Surgery and Lung Disease Research Group, Departments of Medicine and Pharmacology, University of Melbourne, Parkville, Victoria, Australia

Regulatory T cells (Tregs) are a subset of T lymphocytes that are responsible for suppressing the function of other immune cells, and preventing potentially harmful autoimmune responses. Studies in autoimmune-prone mice and human autoimmune diseases have shown reduced Treg number or function as a causative factor for the apparent loss of tolerance that contributes to disease. We have found that Lyn-deficient mice, which develop high titers of autoantibodies with age, have a perturbed Treg compartment. Contrary to what has been observed in some strains of autoimmune-prone mice, aged Lyn-deficient mice have increased numbers of Tregs. This expansion occurs in the presence of elevated serum IL-2 and diminished TGF-β. Despite expansion of the Treg compartment, Lyn-deficient mice succumb at 1 year of age due to immune complex-mediated glomerulonephritis. We have shown that Lyn is not expressed in Tregs or indeed in any T cell subset, suggesting that the expansion and apparent functional deficiency in Tregs in Lyn-deficient mice is due to extrinsic factors rather than an intrinsic Treg defect. Indeed, using an in vivo colitis model, we have shown that Lyn-deficient Tregs can suppress inflammation. These results suggest that Tregs are expanding in Lyn-deficient mice in an effort to control the autoimmune disease but are simply overwhelmed by the disease process. This study highlights the role of the inflammatory setting in autoimmune disease and its consideration when contemplating the use of Tregs as an autoimmune therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Health and Medical Research Council of Australia. E.T. is supported by an Australian Postgraduate Award from the Australian government, and M.L.H. and D.M.T. are recipients of fellowships from the National Health and Medical Research Council of Australia.

² Current address: Department of Microbiology and Immunology, Life Sciences Centre, Vancouver, British Columbia, Canada.

³ Address correspondence and reprint requests to Dr. Margaret L. Hibbs, Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, P.O. Box 2008 Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail address: Margaret.Hibbs{at}ludwig.edu.au

⁴ Abbreviations used in this paper: SHP-1, Src homology region 2 domain-containing phosphatase 1; ANA, anti-nuclear Abs; IBD, inflammatory bowel disease; MFI, mean fluorescence intensity; SLE, systemic lupus erythematosus; Treg, regulatory T cell; WT, wild type.