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Antigen, in the Presence of TGF-, Induces Up-Regulation of FoxP3^gfp+ in CD4⁺ TCR Transgenic T Cells That Mediate Linked Suppression of CD8⁺ T Cell Responses¹

Judith A. Kapp^2,*,, Kazuhito Honjo, Linda M. Kapp^*, Kelly Goldsmith and R. Pat Bucy

^* Department of Ophthalmology and Department of Pathology, University of Alabama AL 35233-7331

CD4⁺CD25⁺ regulatory T cells (Tregs) inhibit immune responses to a variety of Ags, but their specificity and mechanism of suppression are controversial. This controversy is largely because many studies focused on natural Tregs with undefined specificities and suppression has frequently been measured on polyclonal T cell responses. To address the issue of specificity further, we have bred K^d-specific, CD4⁺ TCR (TCR75) transgenic mice to Foxp3^gfp knockin reporter mice to permit sorting of Tregs with a known specificity. Foxp3^gfp.TCR75 mice did not express significant numbers of natural FoxP3⁺ Tregs expressing the TCR75 transgenes, but FoxP3 expression was induced by stimulating with K^d plus TGF-. The resulting GFP⁺ TCR75 cells were anergic, whereas the GFP^– TCR75 cells proliferated upon restimulation with K^d peptide. Yet both exhibited severely reduced expression of intracellular IFN- and TNF- upon restimulation. GFP⁺, but not GFP^–, TCR75 T cells suppressed responses by naive TCR75 T cells and by nontransgenic spleen cells stimulated with anti-CD3. GFP⁺ TCR75 cells also inhibited polyclonal C57BL/6 anti-K^d CTL responses if the APC expressed K^d and both MHC class I and class II, and responses by OT1 T cells to B6.K^d.OVA but not B6.K^d plus OVA expressing APC, demonstrating linked-suppression of CD8 responses. Thus, Tregs exhibit a greater degree of specificity in vitro than previously appreciated. The observation that Tregs and responder T cells must recognize the same APC provides a mechanistic explanation for the observation that Tregs must be in direct contact with effector T cells to suppress their responses.

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 Grants HL50724 (to R.P.B.) and EY014877 (to J.A.K.) from the National Institutes of Health, from the Research to Prevent Blindness (to J.A.K.), and from the Foundation for Fighting Blindness (to J.A.K.).

² Address correspondence and reprint requests to Dr. Judith A. Kapp, Room W287 Spain Wallace Building, University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35294-2170. E-mail address: jkapp{at}uab.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; FoxP3, forkhead/winged helix transcription factor; ICC, intracellular cytokine; GITR, glucocorticoid-induced TNFR; ₂M, ₂-microglobulin; Tg, transgenic.

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