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J Immunol. 2016 Apr 1;196(7):2995-3005. doi: 10.4049/jimmunol.1501764. Epub 2016 Feb 26.

Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis.

Author information

1
Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and.
2
Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany.
3
Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany; and lars.nitschke@fau.de elisabeth.zinser@uk-erlangen.de.
4
Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany lars.nitschke@fau.de elisabeth.zinser@uk-erlangen.de.

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.

PMID:
26921310
DOI:
10.4049/jimmunol.1501764
[Indexed for MEDLINE]
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