Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis

Yin Hu Wang, Wei Yang, Jing Bo Yang, Yan Jie Jia, Wei Tang, M. Eric Gershwin, William M. Ridgway, Zhe Xiong Lian

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Tregs) play a non-redundant role in control of excessive immune responses, and defects in Tregs have been shown both in patients and murine models of primary biliary cirrhosis (PBC), a progressive autoimmune biliary disease. Herein, we took advantage of a murine model of PBC, the dominant negative transforming growth factor β receptor II (dnTGFβRII) mice, to assess Treg genetic defects and their functional effects in PBC. By using high-resolution microarrays with verification by PCR and protein expression, we found profound and wide-ranging differences between dnTGFβRII and normal, wild type Tregs. Critical transcription factors were down-regulated including Eos, Ahr, Klf2, Foxp1 in dnTGFβRII Tregs. Functionally, dnTGFβRII Tregs expressed an activated, pro-inflammatory phenotype with upregulation of Ccl5, Granzyme B and IFN-γ. Genetic pathway analysis suggested that the primary effect of loss of TGFβ pathway signaling was to down regulate immune regulatory processes, with a secondary upregulation of inflammatory processes. These findings provide new insights into T regulatory genetic defects; aberrations of the identified genes or genetic pathways should be investigated in human PBC Tregs. This approach which takes advantage of biologic pathway analysis illustrates the ability to identify genes/pathways that are affected both independently and dependent on abnormalities in TGFβ signaling. Such approaches will become increasingly useful in human autoimmunity.

Original languageEnglish (US)
Pages (from-to)26-37
Number of pages12
JournalJournal of Autoimmunity
Volume59
DOIs
StatePublished - May 1 2015

Keywords

  • Cholangitis
  • Primary biliary cirrhosis
  • Regulatory T cells
  • Transcription profile and pathway analysis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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