@article {542526,
	title = {Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo.},
	journal = {J Immunol},
	volume = {175},
	number = {5},
	year = {2005},
	month = {2005 Sep 1},
	pages = {3133-9},
	abstract = {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.},
	keywords = {Animals, Antigens, CD, CD4-Positive T-Lymphocytes, Cell Adhesion, Integrin alpha Chains, Interleukin-2, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, rap1 GTP-Binding Proteins, T-Lymphocytes, Helper-Inducer},
	issn = {0022-1767},
	author = {Li, Lequn and Greenwald, Rebecca J and Lafuente, Esther M and Tzachanis, Dimitrios and Berezovskaya, Alla and Freeman, Gordon J and Sharpe, Arlene H and Boussiotis, Vassiliki A}
}
