title: Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis.
abstract: The small adaptor protein growth factor receptor-bound protein 2 (Grb2) modulates and integrates signals from receptors on cellular surfaces in inner signaling pathways. In murine T cells, Grb2 is crucial for amplification of TCR signaling. T cell-specific Grb2(fl/fl) Lckcre(tg) Grb2-deficient mice show reduced T cell numbers due to impaired negative and positive selection. In this study, we found that T cell numbers in Grb2(fl/fl) CD4cre(tg) mice were normal in the thymus and were only slightly affected in the periphery. Ex vivo analysis of CD4(+) Th cell populations revealed an increased amount of Th1 cells within the CD4(+) population of Grb2(fl/fl) CD4cre(tg) mice. Additionally, Grb2-deficient T cells showed a greater potential to differentiate into Th17 cells in vitro. To test whether these changes in Th cell differentiation potential rendered Grb2(fl/fl) CD4cre(tg) mice more prone to inflammatory diseases, we used the murine Th1 cell- and Th17 cell-driven model of experimental autoimmune encephalomyelitis (EAE). In contrast to our expectations, Grb2(fl/fl) CD4cre(tg) mice developed a milder form of EAE. The impaired EAE disease can be explained by the reduced proliferation rate of Grb2-deficient CD4(+) T cells upon stimulation with IL-2 or upon activation by allogeneic dendritic cells, because the activation of T cells by dendritic cells and the subsequent T cell proliferation are known to be crucial factors for the induction of EAE. In summary, Grb2-deficient T cells show defects in T cell development, increased Th1 and Th17 cell differentiation capacities, and impaired proliferation after activation by dendritic cells, which likely reduce the clinical symptoms of EAE.
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Radtke
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and.
authors.forename: Sonja M
authors.identifier: http://orcid.org/0000-0002-5145-1157
authors.initials: SM
authors.lastname: Lacher
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Szumilas
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Sandrock
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Ackermann
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and lars.nitschke@fau.de elisabeth.zinser@uk-erlangen.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany lars.nitschke@fau.de elisabeth.zinser@uk-erlangen.de.
authors.forename: Elisabeth
authors.identifier: http://orcid.org/0000-0002-4369-0668
authors.initials: E
authors.lastname: Zinser
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D051380:GRB2 Adaptor Protein / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D051380:GRB2 Adaptor Protein