title: IL-10 signaling in CD4+ T cells is critical for the pathogenesis of collagen-induced arthritis.
abstract: BACKGROUND
  IL-10 is a very important anti-inflammatory cytokine. However, the role of this cytokine in T cells in the pathogenesis of collagen-induced arthritis is unclear. The purpose of this study was to define the role of IL-10 signaling in T cells in the pathogenesis of collagen-induced arthritis.
  
  
  METHODS
  IL-10 receptor dominant-negative transgenic (Tg) and control mice were immunized with bovine type II collagen to induce arthritis. The severity of arthritis was monitored and examined histologically. T-cell activation and cytokine production were analyzed using flow cytometry. T-cell proliferation was examined by [3H]thymidine incorporation. Antigen-specific antibodies in serum were measured by ELISA. Foxp3 expression in CD4+ regulatory T cells (Tregs) was determined by intracellular staining or Foxp3-RFP reporter mice. The suppressive function of Foxp3+ CD4+ Tregs was determined in vitro by performing a T-cell proliferation assay. The level of IL-17 mRNA in joints was measured by real-time PCR. A two-tailed nonparametric paired test (Wilcoxon signed-rank test) was used to calculate the arthritis and histological scores. Student's paired or unpaired t-test was used for all other statistical analyses (InStat version 2.03 software; GraphPad Software, San Diego, CA, USA).
  
  
  RESULTS
  Blocking IL-10 signaling in T cells rendered mice, especially female mice, highly susceptible to collagen-induced arthritis. T-cell activation and proliferation were enhanced and produced more IFN-γ. The suppressive function of CD4+ Foxp3+ regulatory T cells was significantly impaired in Tg mice because of the reduced ability of Tregs from Tg mice to maintain their levels of Foxp3. This was further confirmed by transferring Foxp3-RFP cells from Tg or wild-type (Wt) mice into a congenic Wt host. The higher level of IL-17 mRNA was detected in inflammatory joints of Tg mice, probably due to the recruitment of IL-17+ γδ T cells into the arthritic joints.
  
  
  CONCLUSIONS
  IL-10 signaling in T cells is critical for dampening the pathogenesis of collagen-induced arthritis by maintaining the function of Tregs and the recruitment of IL-17+ γδ T cells.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520-8031, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Tao
authors.forename: Masahito
authors.initials: M
authors.lastname: Kamanaka
authors.forename: Jianlei
authors.initials: J
authors.lastname: Hao
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Hao
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Joe E
authors.initials: JE
authors.lastname: Craft
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhao
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation; D024043:Collagen Type II; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D024043:Collagen Type II; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D007371:Interferon-gamma