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Functional Adaptive CD4 Foxp3 T Cells Develop in MHC Class II-Deficient Mice¹

Department of Internal Medicine I, University of Ulm, Ulm, Germany

CD4 Foxp3 regulatory T (T_R) cells are well-defined regulator T cells known to develop in the thymus through positive selection by medium-to-high affinity TCR-MHC interactions. We asked whether Foxp3 T_R cells can be generated in the complete absence of MHC class II molecules. CD4 Foxp3 T_R cells are found in secondary lymphoid tissues (spleen and lymph nodes) and peripheral tissues (liver) but not the thymus of severely MHC class II-deficient (A^–/– B6) mice. These T_R cells preferentially express CD103 (but not CD25) but up-regulate CD25 surface expression to high levels in response to TCR-mediated activation. MHC class II-independent Foxp3 T_R cells down modulate vaccine-induced, specific antiviral CD8 T cell responses of A^–/– B6 mice in vivo. Furthermore, these T_R cells suppress IL-2 release and proliferative responses in vitro of naive CD25^– (CD4 or CD8) T cells from normal B6 mice primed by bead-coupled anti-CD3/anti-CD28 Ab as efficiently as CD4CD25^high T_R cells from congenic, normal B6 mice. MHC class II-independent CD4 Foxp3⁺ T_R cells thus preferentially express the (TGF--induced) integrin molecule _E (CD103), are generated mainly in the periphery and efficiently mediate immunosuppressive effects.

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 Grant Rei 549/10-2 from Deutsche Forschungsgemeinschaft (to J.R.).

² Address correspondence and reprint requests to Dr. Joerg Reimann, Department of Internal Medicine I, University of Ulm, Albert Einstein Allee 11, D-89081 Ulm, Germany, E-mail address: joerg.reimann{at}uni-ulm.de

³ Abbreviations used in this paper: T_R, regulatory T; wt, wild type; DC, dendritic cell; S, spleen; SP; single-positive CD4⁺CD8^–; DP, double-positive CD4⁺CD8⁺; FCM, flow cytometry; GalCer, -galactosylceramide; HBsAg, hepatitis B surface Ag; ODN, oligodeoxynucleotide.

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