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Atypical Memory Phenotype T Cells with Low Homeostatic Potential and Impaired TCR Signaling and Regulatory T Cell Function in Foxn1^/ Mutant Mice¹

Department of Genetics, University of Georgia, Athens, GA 30602

Foxn1^/ mutants have a block in thymic epithelial cell differentiation at an intermediate progenitor stage, resulting in reduced thymocyte cellularity and blocks at the double-negative and double-positive stages. Whereas naive single-positive thymocytes were reduced >500-fold in the adult Foxn1^/ thymus, peripheral T cell numbers were reduced only 10-fold. The current data shows that Foxn1^/ peripheral T cells had increased expression of activation markers and the ability to produce IL-2 and IFN-. These cells acquired this profile immediately after leaving the thymus as early as the newborn stage and maintained high steady-state proliferation in vivo but decreased proliferation in response to TCR stimulation in vitro. Single-positive thymocytes and naive T cells also had constitutively low βTCR and IL7R expression. These cells also displayed reduced ability to undergo homeostatic proliferation and increased rates of apoptosis. Although the frequency of Foxp3⁺CD4⁺CD25⁺ T cells was normal in Foxn1^/ mutant mice, these cells failed to have suppressor function, resulting in reduced regulatory T cell activity. Recent data from our laboratory suggest that T cells in the Foxn1^/ thymus develop from atypical progenitor cells via a noncanonical pathway. Our results suggest that the phenotype of peripheral T cells in Foxn1^/ mutant mice is the result of atypical progenitor cells developing in an abnormal thymic microenvironment with a deficient TCR and IL7 signaling system.

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, National Institute of Allergy and Infectious Disease Grant AI055001 (to N.R.M.).

² Current address: Department of Biomedical Research, University of Texas Health Center, Tyler, TX 75708.

³ Address correspondence and reprint requests to Dr. Nancy R. Manley, Department of Genetics, S270B Coverdell Center, 500 D. W. Brooks Drive, University of Georgia, Athens, GA 30602. E-mail address: nmanley{at}uga.edu

⁴ Abbreviations used in this paper: TEC, thymic epithelial cell; AC, accessory cell; DN, double negative; E, embryonic day; LN, lymph node; SP, single positive; Treg, regulatory T (cell).

This article has been cited by other articles:

				S. Xiao, D.-m. Su, and N. R. Manley T Cell Development from Kit-Negative Progenitors in the Foxn1{Delta}/{Delta} Mutant Thymus J. Immunol., January 15, 2008; 180(2): 914 - 921. [Abstract] [Full Text] [PDF]