Regulatory T cell-derived IL-10 ameliorates crescentic GN.

Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10-producing Foxp3(+) T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3(+) Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNγ and IL-17; these IL-10-deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.

[1]  U. Panzer,et al.  Immature renal dendritic cells recruit regulatory CXCR6(+) invariant natural killer T cells to attenuate crescentic GN. , 2012, Journal of the American Society of Nephrology : JASN.

[2]  U. Panzer,et al.  Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis. , 2012, Kidney international.

[3]  E. Rosser,et al.  Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis , 2012, Arthritis Research & Therapy.

[4]  D. Vignali,et al.  The battle against immunopathology: infectious tolerance mediated by regulatory T cells , 2011, Cellular and Molecular Life Sciences.

[5]  S. Sakaguchi,et al.  Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. , 2011, Seminars in immunology.

[6]  A. Cope,et al.  The Th1 life cycle: molecular control of IFN-γ to IL-10 switching. , 2011, Trends in immunology.

[7]  R. Caspi,et al.  Faculty Opinions recommendation of Fate mapping of IL-17-producing T cells in inflammatory responses. , 2011 .

[8]  M. Hickey,et al.  Endogenous foxp3(+) T-regulatory cells suppress anti-glomerular basement membrane nephritis. , 2011, Kidney international.

[9]  U. Panzer,et al.  Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis , 2011, Kidney international.

[10]  A. Rudensky,et al.  Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. , 2011, Immunity.

[11]  Francis J. Huber,et al.  Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. , 2011, Immunity.

[12]  G. Mayer,et al.  IL-9 Production by Regulatory T Cells Recruits Mast Cells That Are Essential for Regulatory T Cell-Induced Immune Suppression , 2011, The Journal of Immunology.

[13]  G. Mayer,et al.  Cell-Induced Immune Suppression Mast Cells That Are Essential for Regulatory T IL-9 Production by Regulatory T Cells Recruits , 2011 .

[14]  A. Liston,et al.  Regulatory T Cells , 2011, Methods in Molecular Biology.

[15]  W. B. Reeves,et al.  Endogenous IL-10 Attenuates Cisplatin Nephrotoxicity: Role of Dendritic Cells , 2010, The Journal of Immunology.

[16]  Clare A. Notley,et al.  The yin and yang of regulatory T cells and inflammation in RA , 2010, Nature Reviews Rheumatology.

[17]  Thomas Korn,et al.  Proinflammatory T helper type 17 cells are effective B-cell helpers , 2010, Proceedings of the National Academy of Sciences.

[18]  U. Panzer,et al.  CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. , 2010, Journal of the American Society of Nephrology : JASN.

[19]  G. Mayer,et al.  CCR7 deficiency exacerbates injury in acute nephritis due to aberrant localization of regulatory T cells. , 2010, Journal of the American Society of Nephrology : JASN.

[20]  D. Vignali,et al.  Regulatory T cells and inhibitory cytokines in autoimmunity. , 2009, Current opinion in immunology.

[21]  Gisen Kim,et al.  Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis , 2009, Nature Immunology.

[22]  S. Sakaguchi,et al.  Regulatory T cells: how do they suppress immune responses? , 2009, International immunology.

[23]  Liping Huang,et al.  Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. , 2009, Journal of the American Society of Nephrology : JASN.

[24]  E. Shevach.  Mechanisms of foxp3+ T regulatory cell-mediated suppression. , 2009, Immunity.

[25]  U. Panzer,et al.  The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. , 2009, Journal of the American Society of Nephrology : JASN.

[26]  D. Littman,et al.  Identification of IL-17-producing FOXP3+ regulatory T cells in humans , 2009, Proceedings of the National Academy of Sciences.

[27]  U. Panzer,et al.  CCR5 Deficiency Aggravates Crescentic Glomerulonephritis in Mice1 , 2008, The Journal of Immunology.

[28]  C. Baecher-Allan,et al.  Multiple Sclerosis and Regulatory T Cells , 2008, Journal of Clinical Immunology.

[29]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

[30]  D. Riethmacher,et al.  In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells , 2008, The Journal of experimental medicine.

[31]  E. Chi,et al.  Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. , 2008, Immunity.

[32]  L. Marnell,et al.  C-Reactive Protein-Mediated Suppression of Nephrotoxic Nephritis: Role of Macrophages, Complement, and Fcγ Receptors1 , 2007, The Journal of Immunology.

[33]  L. Marnell,et al.  C-reactive protein-mediated suppression of nephrotoxic nephritis: role of macrophages, complement, and Fcgamma receptors. , 2007, Journal of immunology.

[34]  Werner Müller,et al.  Interleukin‐10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA , 2006, European journal of immunology.

[35]  F. Sutterwala,et al.  Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. , 2006, Immunity.

[36]  F. Powrie,et al.  Characterization of Foxp3+CD4+CD25+ and IL-10-Secreting CD4+CD25+ T Cells during Cure of Colitis1 , 2006, The Journal of Immunology.

[37]  H. Tilg,et al.  CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. , 2005, Journal of the American Society of Nephrology : JASN.

[38]  H. Cantor,et al.  Regulatory T cells and autoimmune disease , 2005, Immunological reviews.

[39]  F. Powrie,et al.  Interleukin-10 in the regulation of T cell-induced colitis. , 2003, Journal of autoimmunity.

[40]  I. Anegon,et al.  Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  P. Tipping,et al.  Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis. , 2000, Kidney international.

[42]  Fiona Powrie,et al.  An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation , 1999, The Journal of experimental medicine.

[43]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[44]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.