Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis.
Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis.
复制标题
小鼠原发性胆汁性肝硬化T调节细胞遗传通路的系统生物学分析
DOI：
10.1016/j.jaut.2015.01.011
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发表时间：
2015-05
影响因子：
12.8
通讯作者：
Lian ZX
中科院分区：
文献类型：
--
作者：
Wang YH;Yang W;Yang JB;Jia YJ;Tang W;Gershwin ME;Ridgway WM;Lian ZX
CD4+Foxp3+ 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.
