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A Major Role for Bim in Regulatory T Cell Homeostasis
This information is current as of July 13, 2011 Claire A. Chougnet, Pulak Tripathi, Celine S. Lages, Jana Raynor, Allyson Sholl, Pamela Fink, David R. Plas and David A. Hildeman J Immunol 2011;186;156-163; Prepublished online 22 November 2010; doi:10.4049/jimmunol.1001505 http://www.jimmunol.org/content/186/1/156
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http://www.jimmunol.org/content/suppl/2010/11/22/jimmunol.10015 05.DC1.html This article cites 54 articles, 28 of which can be accessed free at: http://www.jimmunol.org/content/186/1/156.full.html#ref-list-1 Information about subscribing to The Journal of Immunology is online athttp://www.jimmunol.org/subscriptions Submit copyright permission requests at http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at http://www.jimmunol.org/etoc/subscriptions.shtml/

The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright ©2011 by TheAmerican Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.

The Journal of Immunology

A Major Role for Bim in Regulatory T Cell Homeostasis
Claire A. Chougnet,* Pulak Tripathi,† Celine S. Lages,* Jana Raynor,† Allyson Sholl,† Pamela Fink,‡ David R. Plas,x and David A. Hildeman†
We have previously shown that regulatory T cells (Treg)accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion. Instead, we foundthat Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Ra, we found that IL-7R signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the proapoptotic molecule Bim compared with Treg from young mice. Furthermore, in the absence of Bim, Tregaccumulate rapidly, accounting for >25% of the CD4+ T cell compartment by 6 mo of age. Additionally, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bimlo Treg. Collectively, our data suggest that chronic stimulation by IL-2 leads topreferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts. The Journal of Immunology, 2011, 186: 156–163. onsiderable changes in the function of T cells, in particular decreased responsiveness of CD4+ and CD8+ T cells, have been reported in aged hosts (mice and humans). T cells from aged mice and humans exhibit serious defects inTCR-mediated activation, including changes in the cascades of serine/threonine and tyrosine phosphorylation and trouble forming functional immune synapses with APCs (1–4). Furthermore, many functional defects have been reported in vivo, as evidenced by the decreased ability of aged hosts to control many infections (reviewed in Ref. 5). Although a number of the defects described in senescent CD4+ and CD8+T cells appear to be intrinsic (reviewed in Ref. 6), recent lines of evidence have suggested that the changed balance between effector and regulatory T cells may play a major role in decreased T cell responses in aged hosts. Regulatory T cells (Treg), a subset of CD4+ T cells, are critical for maintaining self-tolerance (7). Treg dampen effector responses against persistent infections (8) and...