title: Differential Levels of Tl1a Affect the Expansion and Function of Regulatory T Cells in Modulating Murine Colitis.
abstract: BACKGROUND
  Expression of TL1A (tumor necrosis factor-like ligand 1A) is increased in patients with inflammatory bowel disease (IBD). Mice with elevated T-cell expression of Tl1a (L-Tg) have increased regulatory T cells, yet develop worsened colitis and intestinal fibrosis. The aim of this study was to investigate the role of Tl1a in the differentiation and function of Tregs and their effects in modulating murine colitis.
  
  
  METHODS
  Tl1a overexpressing L-Tg, Foxp3-mRFP (FIR)-LTg, and DR3KO-LTg mice were used for the study. In the L-Tg mice, Tl1a expressing cells can be identified by green fluorescent protein (GFP).
  
  
  RESULTS
  We report that Foxp3 expression in the L-Tg mice is variable based on high or low level of Tl1a expression, referred to herein as GFPhigh and GFPlow T cells. Treg-specific suppressive molecules were highly expressed on the GFPlow Foxp3 Tregs and were significantly reduced on Tregs expressing high Tl1a. In vitro suppression function was significantly enhanced in the GFPlow compared with the GFPhigh Tregs. RAG mice cotransferred with either GFPlow or wild-type Tregs were protected from colitis. Furthermore, GFPlow Tregs lost the suppression function in the absence of DR3 (Death receptor 3).
  
  
  CONCLUSIONS
  Tregs expressing low levels of Tl1a ameliorate murine colitis and promote the maintenance of Treg suppressor function in a DR3-dependent manner, partly due to a heightened regulatory program. These data reveal novel roles for differential levels of Tl1a in regulating T cell-mediated immune responses that have implications in understanding the pathogenesis of IBD.
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Maninder
authors.initials: M
authors.lastname: Sidhu-Varma
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D012333:RNA, Messenger; D053219:Receptors, Tumor Necrosis Factor, Member 25; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
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