%0 Journal Article %J J Immunol %D 2005 %T Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo. %A Li, Lequn %A Greenwald, Rebecca J %A Lafuente, Esther M %A Tzachanis, Dimitrios %A Berezovskaya, Alla %A Freeman, Gordon J %A Sharpe, Arlene H %A Boussiotis, Vassiliki A %K Animals %K Antigens, CD %K CD4-Positive T-Lymphocytes %K Cell Adhesion %K Integrin alpha Chains %K Interleukin-2 %K Lymphocyte Activation %K Lymphocyte Function-Associated Antigen-1 %K Mice %K Mice, Inbred C57BL %K Mitogen-Activated Protein Kinase 1 %K Mitogen-Activated Protein Kinase 3 %K rap1 GTP-Binding Proteins %K T-Lymphocytes, Helper-Inducer %X 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. %B J Immunol %V 175 %P 3133-9 %8 2005 Sep 1 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/16116203?dopt=Abstract