Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
J Clin Invest ; 125(11): 4011-20, 2015 Nov 02.
Article in English | MEDLINE | ID: mdl-26413871

ABSTRACT

IL-17-producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/physiopathology , Interleukin-21 Receptor alpha Subunit/physiology , Interleukins/physiology , Th17 Cells/immunology , Animals , Antigen Presentation , Cells, Cultured , Disease Susceptibility , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-21 Receptor alpha Subunit/deficiency , Interleukin-21 Receptor alpha Subunit/genetics , Lymphocyte Activation , Lymphopoiesis , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myelin-Oligodendrocyte Glycoprotein/immunology , Peptide Fragments/immunology , Receptors, Interleukin/biosynthesis , Receptors, Interleukin/deficiency , Receptors, Interleukin/genetics , Signal Transduction , Specific Pathogen-Free Organisms
2.
J Exp Med ; 210(3): 433-43, 2013 Mar 11.
Article in English | MEDLINE | ID: mdl-23440042

ABSTRACT

Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.


Subject(s)
Immunologic Deficiency Syndromes/genetics , Interleukin-21 Receptor alpha Subunit/genetics , Mutation , Child , Child, Preschool , Female , Humans , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/immunology , Interleukin-21 Receptor alpha Subunit/chemistry , Interleukin-21 Receptor alpha Subunit/physiology , Killer Cells, Natural/immunology , Male , Phosphorylation , STAT3 Transcription Factor/metabolism , Signal Transduction
3.
J Immunol ; 189(2): 1081-93, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22723520

ABSTRACT

T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12→B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft-versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis.


Subject(s)
B-Lymphocyte Subsets/immunology , CD4-Positive T-Lymphocytes/immunology , Graft vs Host Disease/immunology , Interleukin-21 Receptor alpha Subunit/physiology , Interleukins/physiology , Lupus Erythematosus, Systemic/immunology , Animals , B-Lymphocyte Subsets/pathology , CD4-Positive T-Lymphocytes/pathology , Cell Differentiation/genetics , Cell Differentiation/immunology , Chronic Disease , Down-Regulation/genetics , Down-Regulation/immunology , Graft vs Host Disease/complications , Graft vs Host Disease/pathology , Interleukin-21 Receptor alpha Subunit/biosynthesis , Interleukin-21 Receptor alpha Subunit/deficiency , Interleukins/biosynthesis , Lupus Erythematosus, Systemic/etiology , Lupus Erythematosus, Systemic/pathology , Lymphocyte Cooperation/genetics , Lymphocyte Cooperation/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Th17 Cells/immunology , Th17 Cells/pathology , Up-Regulation/genetics , Up-Regulation/immunology
4.
Immunity ; 36(6): 1060-72, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22579473

ABSTRACT

It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have shown that dendritic cells (DCs) in the pancreas required IL-21R not for antigen uptake, but to acquire the chemokine receptor CCR7 and migrate into the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) class II, and CD86 was provided to autoreactive effector cells in Il21r(-/-) mice, impairing CD4(+) T cell activation, CD40:CD40L interactions, and pancreatic infiltration by autoreactive T cells. CD40 crosslinking restored defective CD4(+) cell expansion and CD4 independently expanded autoreactive CD8(+) cells, but CD8(+) cells still required CD4(+) cells to reach the pancreas and induce diabetes. Diabetes induction by transferred T cells required IL-21R-sufficient host antigen-presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r(-/-) mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4(+) cells for autoreactive CD8(+) cells to reach the islets.


Subject(s)
Autoimmunity/immunology , Diabetes Mellitus, Type 1/immunology , Interleukin-21 Receptor alpha Subunit/physiology , Islets of Langerhans/immunology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Animals , Antigen Presentation , CD4-Positive T-Lymphocytes/immunology , CD40 Antigens/immunology , CD40 Ligand/immunology , CD8-Positive T-Lymphocytes/immunology , Chemotaxis, Leukocyte , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Disease Resistance , Interleukin-21 Receptor alpha Subunit/deficiency , Interleukin-21 Receptor alpha Subunit/genetics , Lymph Nodes/immunology , Lymph Nodes/pathology , Lymphocyte Activation , Lymphocyte Cooperation , Lymphocytic choriomeningitis virus , Mice , Mice, Inbred NOD , Receptors, CCR7/metabolism , Specific Pathogen-Free Organisms , Spleen/immunology , T-Lymphocyte Subsets/transplantation
5.
Blood ; 118(2): 446-55, 2011 Jul 14.
Article in English | MEDLINE | ID: mdl-21596854

ABSTRACT

IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.


Subject(s)
Graft vs Host Disease/genetics , Graft vs Leukemia Effect/genetics , Immunity, Innate/genetics , Interleukins/physiology , T-Lymphocytes/metabolism , Tissue Donors , Animals , Gene Knockdown Techniques , Graft vs Host Disease/immunology , Graft vs Host Disease/metabolism , Humans , Immunity, Innate/physiology , Interleukin-21 Receptor alpha Subunit/genetics , Interleukin-21 Receptor alpha Subunit/metabolism , Interleukin-21 Receptor alpha Subunit/physiology , Interleukins/genetics , Interleukins/metabolism , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Organ Specificity/genetics , Organ Specificity/immunology , Signal Transduction/genetics , T-Lymphocytes/physiology , Transplantation Immunology
6.
J Immunol ; 185(3): 1920-6, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20574002

ABSTRACT

We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4(+) T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell infiltration into the liver and intestine, leading to prolonged survival. After transplantation, CD4(+) T cell numbers in the spleen were reduced, and MLR and cytokine production by CD4(+) T cells were impaired. These results suggest that IL-21 might promote GVHD through enhanced production of effector CD4(+) T cells. Moreover, we found that CD25 depletion altered neither the impaired MLR in vitro nor the ameliorated GVHD symptoms in vivo. Thus, the attenuated GVHD might be caused by an impairment of effector T cell differentiation itself, rather than by an increase in regulatory T cells and suppression of effector T cells.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Gene Deletion , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Interleukin-21 Receptor alpha Subunit/deficiency , Interleukin-21 Receptor alpha Subunit/genetics , Animals , Bone Marrow Transplantation/immunology , Bone Marrow Transplantation/pathology , CD4-Positive T-Lymphocytes/transplantation , Cell Movement/genetics , Cell Movement/immunology , Cells, Cultured , Female , Graft vs Host Disease/prevention & control , Immunophenotyping , Inflammation Mediators/physiology , Interleukin-21 Receptor alpha Subunit/physiology , Interleukins/physiology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout
7.
Exp Hematol ; 38(5): 373-83, 2010 May.
Article in English | MEDLINE | ID: mdl-20193734

ABSTRACT

OBJECTIVE: Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin's lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells. MATERIALS AND METHODS: IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin-V-propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot. RESULTS: IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21-mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R-positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21-responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression. CONCLUSION: These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21-mediated effects in some FL cells.


Subject(s)
Apoptosis/drug effects , Interleukin-21 Receptor alpha Subunit/physiology , Interleukins/physiology , Lymphoma, Follicular/pathology , Cell Line, Tumor/cytology , Cell Line, Tumor/drug effects , Chromosomes, Human, Pair 14/ultrastructure , Chromosomes, Human, Pair 18/ultrastructure , Gene Expression Regulation, Neoplastic/drug effects , Humans , Interleukin-21 Receptor alpha Subunit/biosynthesis , Interleukin-21 Receptor alpha Subunit/drug effects , Interleukins/pharmacology , Janus Kinase 3/deficiency , Janus Kinases/physiology , Lymphoma, Follicular/genetics , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , STAT Transcription Factors/physiology , Signal Transduction/drug effects , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/biosynthesis , Suppressor of Cytokine Signaling Proteins/genetics , Translocation, Genetic
SELECTION OF CITATIONS
SEARCH DETAIL
...