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The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.

Publication ,  Journal Article
O'Brien, SA; Zhu, M; Zhang, W
Published in: J Immunol
July 15, 2015

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is highly tyrosine phosphorylated upon engagement of the TCR. Phosphorylated LAT binds Grb2, Gads, and phospholipase C (PLC)γ1 to mediate T cell activation, proliferation, and cytokine production. T cells from mice harboring a mutation at the PLCγ1 binding site of LAT (Y136F) have impaired calcium flux and Erk activation. Interestingly, these T cells are highly activated, resulting in the development of a lymphoproliferative syndrome in these mice. CD4(+) T cells in LATY136F mice are Th2 skewed, producing large amounts of IL-4. In this study, we showed that the LATY136F T cells could also overproduce IL-6 due to activated NF-κB, AKT, and p38 pathways. By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development. Reduced CD4(+) T cell expansion was not due to a further block in thymocyte development or an increase in the number of regulatory T cells, but was caused by reduction in cell survival. In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished. Our data indicated that the LAT-PLCγ1 interaction is important for controlling IL-6 production by T cells and demonstrated a critical role of IL-6 in the development of this lymphoproliferative syndrome.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

July 15, 2015

Volume

195

Issue

2

Start / End Page

695 / 705

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Splenomegaly
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Binding
  • Primary Cell Culture
  • Phosphoproteins
  • Phospholipase C gamma
  • NF-kappa B
  • Mice, Knockout
 

Citation

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Chicago
ICMJE
MLA
NLM
O’Brien, S. A., Zhu, M., & Zhang, W. (2015). The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity. J Immunol, 195(2), 695–705. https://doi.org/10.4049/jimmunol.1403187
O’Brien, Sarah A., Minghua Zhu, and Weiguo Zhang. “The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.J Immunol 195, no. 2 (July 15, 2015): 695–705. https://doi.org/10.4049/jimmunol.1403187.
O’Brien SA, Zhu M, Zhang W. The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity. J Immunol. 2015 Jul 15;195(2):695–705.
O’Brien, Sarah A., et al. “The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.J Immunol, vol. 195, no. 2, July 2015, pp. 695–705. Pubmed, doi:10.4049/jimmunol.1403187.
O’Brien SA, Zhu M, Zhang W. The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity. J Immunol. 2015 Jul 15;195(2):695–705.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

July 15, 2015

Volume

195

Issue

2

Start / End Page

695 / 705

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Splenomegaly
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Binding
  • Primary Cell Culture
  • Phosphoproteins
  • Phospholipase C gamma
  • NF-kappa B
  • Mice, Knockout