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* Division of Molecular Immunology and
Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Center for Epidemiology and Biostatistics, Children’s Hospital Medical Center, Cincinnati, OH 45229; and
¶ Office of Geriatric Medicine, University of Cincinnati, Cincinnati, OH 45267
Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (Tregs), a CD4+ T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all Tregs, especially in aged hosts, we characterized Tregs by the expression of FOXP3, a transcription factor crucial for Treg differentiation and function. The proportion of FOXP3+CD4+ Tregs increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3+ Tregs from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral Tregs from elderly humans improves effector T cell responses in most subjects. Importantly, Tregs from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young Tregs. The increased proportion of Tregs in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old Tregs efficiently suppressed the production of IFN-
by effector T cells. Finally, in vivo depletion of Tregs in old mice attenuated disease severity. Accumulation of functional Tregs in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of Treg numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.
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 study was supported by National Institutes of Health Grant AG025149 (to C.C.), the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to Y.B.), and a Colciencias fellowship (to P.A.V.).
2 C.S.L. and I.S. contributed equally to this work; Y.B. and C.C. are equal senior coauthors.
3 Current address: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
4 Current address: Immunovirology Group, University of Antioquia, Colombia.
5 Address correspondence and reprint requests to Dr. Claire Chougnet, Division of Molecular Immunology (ML 7021), Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address: Claire.Chougnet{at}cchmc.org
6 Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; FoxP3, Forkhead box P3; GITR, glucocorticoid-induced TNFR-associated protein; LN, lymph node; mLN, mesenteric lymph node; MFI, mean fluorescence intensity; PD-1, programmed death-1; pLN, peripheral lymph node (retromaxillary and popliteal); Teff, effector T cell.
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