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Rap1-GTP Is a Negative Regulator of Th Cell Function and Promotes the Generation of CD4⁺CD103⁺ Regulatory T Cells In Vivo¹

Lequn Li^2,*, Rebecca J. Greenwald, Esther M. Lafuente^2,*, Dimitrios Tzachanis^*, Alla Berezovskaya^*, Gordon J. Freeman^*, Arlene H. Sharpe and Vassiliki A. Boussiotis^3,*

^* Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115

The small GTPase Rap1 is transiently activated during TCR ligation and regulates integrin-mediated adhesion. To understand the in vivo functions of Rap1 in regulating T cell immune responses, we generated transgenic (Tg) mice, which express the active GTP-bound mutant Rap1E63 in their T lymphocytes. Although Rap1E63-Tg T cells exhibited increased LFA-1-mediated adhesion, ERK1/2 activation and proliferation of Rap1E63-Tg CD4⁺ T cells were defective. Rap1E63-Tg T cells primed in vivo and restimulated with specific Ag in vitro, exhibited reduced proliferation and produced reduced levels of IL-2. Rap1E63-Tg mice had severely deficient T cell-dependent B cell responses, as determined by impaired Ig class switching. Rap1E63-Tg mice had an increased fraction of CD4⁺CD103⁺ regulatory T cells (Treg), which exhibited enhanced suppressive efficiency as compared with CD4⁺CD103⁺ Treg from normal littermate control mice. Depletion of CD103⁺ Treg significantly restored the impaired responses of Rap1E63-Tg CD4⁺ T cells. Thus Rap1-GTP is a negative regulator of Th cell responses and one mechanism responsible for this effect involves the increase of CD103⁺ Treg cell fraction. Our results show that Rap1-GTP promotes the generation of CD103⁺ Treg and may have significant implications in the development of strategies for in vitro generation of Treg for the purpose of novel immunotherapeutic approaches geared toward tolerance induction.

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