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Environmental and Intrinsic Factors Lead to Antigen Unresponsiveness in CD4⁺ Recent Thymic Emigrants from Aged Mice¹

Trudeau Institute, Saranac Lake, NY 12983

Naive CD4 cells from aged mice respond inefficiently to Ag, but the factors that underlie the age-associated defects remain unclear. We have used two approaches to isolate recent thymic emigrants (RTE) in young and aged mice and have compared their capacity to respond to antigenic stimulation ex vivo. An in situ intrathymic CFSE injection labeled developing thymocytes and allowed the identification of RTE in secondary lymphoid tissues. Analysis of CFSE-labeled RTE and control unlabeled naive CD4 cells indicated that cells from aged mice were defective in their ability to increase intracellular Ca²⁺ concentration following TCR cross-linking. Aged naive and RTE CD4 also secreted less IL-2 and proliferated less than that of comparable young CD4 populations. Defects in effector generation in aged RTE were overcome by the addition of IL-2 to cultures. RTE from both polyclonal and TCR transgenic mice were compromised, indicating that defects were independent of TCR specificity. In the second model, the cotransfer of congenic marker-labeled young and aged BM cells into young and aged syngeneic hosts revealed that hyporesponsiveness in aged RTE was caused by a combination of defects intrinsic to CD4 progenitors and defects induced by the aged environment. Depletion of peripheral CD4 cells in aged mice led to production of new RTE that were not defective. The results of this study suggest that defects induced by environmental and lineage intrinsic factors act together to reduce responses to Ag in aged naive CD4 cells and that these defects can be overcome in aged CD4 cells produced during recovery from lymphopenia.

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 by National Institutes of Health Grants AG025805 and AG021600 and the Trudeau Institute.

² Address correspondence and reprint requests to Dr. Susan L. Swain, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: sswain{at}northnet.org

³ Abbreviations used in this paper: BM, bone marrow; RTE, recent thymic emigrant; BM-RTE, BM-derived RTE; [Ca²⁺]i, intracellular Ca²⁺; Rh123, rhodamine 123; Tg, transgenic.

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				S. C. Jones, K. Clise-Dwyer, G. Huston, J. Dibble, S. Eaton, L. Haynes, and S. L. Swain Impact of Post-Thymic Cellular Longevity on the Development of Age-Associated CD4+ T Cell Defects J. Immunol., April 1, 2008; 180(7): 4465 - 4475. [Abstract] [Full Text] [PDF]