Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo.
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.
Li
Lequn
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Greenwald
Rebecca J
RJ
Lafuente
Esther M
EM
Tzachanis
Dimitrios
D
Berezovskaya
Alla
A
Freeman
Gordon J
GJ
Sharpe
Arlene H
AH
Boussiotis
Vassiliki A
VA
D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion; D039001:Integrin alpha Chains / Q000032:analysis*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D015703:Antigens, CD; D039001:Integrin alpha Chains; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; C091367:alpha E integrins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020827:rap1 GTP-Binding Proteins