@article {Li3133, 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.}, title = {Rap1-GTP Is a Negative Regulator of Th Cell Function and Promotes the Generation of CD4+CD103+ Regulatory T Cells In Vivo}, volume = {175}, number = {5}, pages = {3133--3139}, year = {2005}, doi = {10.4049/jimmunol.175.5.3133}, publisher = {American Association of Immunologists}, 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.}, issn = {0022-1767}, URL = {https://www.jimmunol.org/content/175/5/3133}, eprint = {https://www.jimmunol.org/content/175/5/3133.full.pdf}, journal = {The Journal of Immunology} }