Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease.

Interleukin (IL)-15 contributes to the immunopathogenesis of Celiac disease (CD). However, it is not clear how IL-15 affects APC that shape adaptive immune responses to the dietary antigen, gliadin. Using PBMC from healthy individuals, we show that monocytes differentiated with IL-15 (IL15-DC) produced IL-1beta, IL-6, IL-15, IL-23, TNFalpha and CCL20 in response to pepsin-trypsin digested gliadin (PTG) and activated contact-dependent Th17 and Th1 responses from autologous CD4(+) T cells. Lower concentrations of IL-15 augmented IFNgamma responses to PTG in PBMC from CD patients compared to controls. Thus, IL-15 supports Th17 and Th1 responses to a dietary antigen that is normally well-tolerated in healthy individuals by generating IL15-DC. These potentially pathogenic immune responses may result in CD patients and not healthy individuals as a consequence of IL-15 hypersensitivity. Therefore, genetic and/or environmental factors that control IL-15 expression and responsiveness in the intestine likely participate in the pathogenesis of CD.

[1]  Graham M Lord,et al.  Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes , 2007, Proceedings of the National Academy of Sciences.

[2]  Tetsuro Takayama,et al.  Human CD14+ Macrophages in Intestinal Lamina Propria Exhibit Potent Antigen-Presenting Ability1 , 2009, The Journal of Immunology.

[3]  Lu Shan,et al.  Structural Basis for Gluten Intolerance in Celiac Sprue , 2002, Science.

[4]  T. Mcclanahan,et al.  #2202: Mucosal Autoimmunity Saturday, June 13 10:45 am–11:00 amCirculating and Gut-resident Human Th17 Cells Express CD161 and Promote Intestinal Inflammation , 2009 .

[5]  Link,et al.  IL‐15 mRNA expression is up‐regulated in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis (MS) , 1998, Clinical and experimental immunology.

[6]  Marc Chanson,et al.  Airway epithelial IL-15 transforms monocytes into dendritic cells. , 2007, American journal of respiratory cell and molecular biology.

[7]  T. Hibi,et al.  Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. , 2008, Journal of Clinical Investigation.

[8]  N. Yawalkar,et al.  Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis. , 2009, Journal of dermatological science.

[9]  Graham M Lord,et al.  In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses , 2009, Proceedings of the National Academy of Sciences.

[10]  D. Jarrossay,et al.  Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells , 2009, Nature Immunology.

[11]  D. Jarrossay,et al.  Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells , 2007, Nature Immunology.

[12]  Paul Rutgeerts,et al.  IL-15 Is Highly Expressed in Inflammatory Bowel Disease and Regulates Local T Cell-Dependent Cytokine Production1 , 2000, The Journal of Immunology.

[13]  D. Jewell,et al.  T cells in peripheral blood after gluten challenge in coeliac disease , 2005, Gut.

[14]  E. Thorsby,et al.  T Cells from the Peripheral Blood of Coeliac Disease Patients Recognize Gluten Antigens when Presented by HLA‐DR, ‐DQ, or ‐DP Molecules , 1994, Scandinavian journal of immunology.

[15]  B. Wierusz-Wysocka,et al.  IL-15 is elevated in serum patients with type 1 diabetes mellitus. , 2005, Diabetes research and clinical practice.

[16]  E. Martı́n-Mola,et al.  A Dual Action of Rheumatoid Arthritis Synovial Fibroblast IL-15 Expression on the Equilibrium between CD4+CD25+ Regulatory T Cells and CD4+CD25− Responder T Cells1 , 2009, The Journal of Immunology.

[17]  James T. Elder.  IL-15 and psoriasis: another genetic link to Th17? , 2007, The Journal of investigative dermatology.

[18]  F. Powrie,et al.  Interleukin-23 drives innate and T cell–mediated intestinal inflammation , 2006, The Journal of experimental medicine.

[19]  D. Mann,et al.  Cutting Edge: IL-1 Controls the IL-23 Response Induced by Gliadin, the Etiologic Agent in Celiac Disease1 , 2008, The Journal of Immunology.

[20]  N. Cerf-Bensussan,et al.  Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease. , 2007, Gastroenterology.

[21]  John E. Connolly,et al.  IL‐15‐induced human DC efficiently prime melanoma‐specific naive CD8+ T cells to differentiate into CTL , 2007, European journal of immunology.

[22]  V. Casolaro,et al.  Differential Mucosal IL-17 Expression in Two Gliadin-Induced Disorders: Gluten Sensitivity and the Autoimmune Enteropathy Celiac Disease , 2009, International Archives of Allergy and Immunology.

[23]  T. Waldmann,et al.  Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes , 2009, Proceedings of the National Academy of Sciences.

[24]  M. Ráki,et al.  A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells. , 2006, Gastroenterology.

[25]  S. Tangye,et al.  Early commitment of naïve human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL‐12 , 2009, Immunology and cell biology.

[26]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[27]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[28]  W. Maśliński,et al.  High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism1 , 2000, The Journal of Immunology.

[29]  W. Buurman,et al.  Presence of inducible nitric oxide synthase, nitrotyrosine, CD68, and CD14 in the small intestine in celiac disease. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[30]  F. Chirdo,et al.  Higher constitutive IL15Rα expression and lower IL‐15 response threshold in coeliac disease patients , 2008, Clinical and experimental immunology.

[31]  N. Cerf-Bensussan,et al.  IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway1 , 2009, The Journal of Immunology.

[32]  V. Raia,et al.  Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease , 2003, The Lancet.

[33]  Nathalie Arbour,et al.  Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation , 2007, Nature Medicine.

[34]  D. Hafler,et al.  Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells1 , 2009, The Journal of Immunology.

[35]  T. Waldmann,et al.  The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells , 2007, Proceedings of the National Academy of Sciences.

[36]  Izortze Santin,et al.  TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin , 2009, Autoimmunity.

[37]  J. Sprent,et al.  Antiviral CD4+ memory T cells are IL-15 dependent , 2007, The Journal of experimental medicine.

[38]  D. Schuppan,et al.  In Vitro Differentiation of Human Monocytes into Dendritic Cells by Peptic–Tryptic Digest of Gliadin Is Independent of Genetic Predisposition and the Presence of Celiac Disease , 2008, Journal of Clinical Immunology.

[39]  G R Corazza,et al.  Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease , 2005, Gut.

[40]  J. McCluskey,et al.  Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-Transgenic Mice Expressing Specific Anti-Gliadin CD4+ T Cells1 , 2009, The Journal of Immunology.

[41]  T. Ottenhoff,et al.  Divergent effects of IL‐12 and IL‐23 on the production of IL‐17 by human T cells , 2006, European journal of immunology.

[42]  E. Martı́n-Mola,et al.  IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate1 , 2004, The Journal of Immunology.