Thomas Korn

Publications of Thomas Korn

• CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

  Authors: Markus C Kowarik, Sabine Cepok, Johann Sellner, Verena Grummel, Martin S Weber, Thomas Korn, Achim Berthele, Bernhard Hemmer

  Journal of neuroinflammation. 05/2012; 9(1):93.

  ABSTRACT: BACKGROUND: The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous systemABSTRACT: BACKGROUND: The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS)compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels. METHODS: Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry. RESULTS: CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with B cells, plasmablasts and intrathecal Ig synthesis. CONCLUSIONS: CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.

• Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011.

  Authors: Christoph Kleinschnitz, Sven G Meuth, Tim Magnus, Thomas Korn, Ralf A Linker

  Experimental & translational stroke medicine. 02/2012; 4(1):2.

  ABSTRACT: From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientificABSTRACT: From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1'st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner's group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012.

• Development and function of interleukin 17-producing γδ T cells.

  Authors: Thomas Korn, Franziska Petermann

  Annals of the New York Academy of Sciences. 01/2012; 1247:34-45.

  Interleukin (IL) 17 is a phylogenetically ancient cytokine that has been adopted by the adaptive immune system, and the investigation of adaptive T helper (Th) 17 cells has substantially contributedInterleukin (IL) 17 is a phylogenetically ancient cytokine that has been adopted by the adaptive immune system, and the investigation of adaptive T helper (Th) 17 cells has substantially contributed to our understanding of the molecular requirements for the induction, regulation, and function of IL-17. However, IL-17 is in fact produced by a large variety of innate immune cells and exerts its most significant biological functions at the interface of the organism with its environment, such as, for example, at epithelial surfaces, where γδ T cells are a prominent source of IL-17. In this review, we will give an overview on the concepts of commitment of γδ T cells to effector phenotypes, focusing on IL-17-producing γδ T cells (γδT17 cells). The role of γδT17 cells in animal models of autoimmunity will be discussed as well as the prerequisites for the development of human γδT17 cells and their potential importance for human disease conditions.

• Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE.

  Authors: Veit Rothhammer, Sylvia Heink, Franziska Petermann, Rajneesh Srivastava, Malte C Claussen, Bernhard Hemmer, Thomas Korn

  The Journal of experimental medicine. 11/2011; 208(12):2465-76.

  The integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS). However, both Th1 and Th17 cells are capable of inducing experimental autoimmuneThe integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS). However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined. We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE. Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG(35-55)-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade. Accordingly, T cell-conditional α4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of IL-23R(+)CCR6(+)CD4(+) T cells. The entry of α4-deficient Th17 cells into the CNS was abolished by blockade of LFA-1 (αLβ2 integrin). Thus, Th1 cells preferentially infiltrate the spinal cord via an α4 integrin-mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLβ2. These observations have implications for the understanding of lesion localization, immunosurveillance, and drug design in multiple sclerosis.

• Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity.

  Authors: Jakob Loschko, Sylvia Heink, Daniela Hackl, Diana Dudziak, Wolfgang Reindl, Thomas Korn, Anne B Krug

  Journal of immunology (Baltimore, Md. : 1950). 11/2011; 187(12):6346-56.

  Plasmacytoid dendritic cells (PDCs) have been shown to present Ags and to contribute to peripheral immune tolerance and to Ag-specific adaptive immunity. However, modulation of adaptive immunePlasmacytoid dendritic cells (PDCs) have been shown to present Ags and to contribute to peripheral immune tolerance and to Ag-specific adaptive immunity. However, modulation of adaptive immune responses by selective Ag targeting to PDCs with the aim of preventing autoimmunity has not been investigated. In the current study, we demonstrate that in vivo Ag delivery to murine PDCs via the specifically expressed surface molecule sialic acid binding Ig-like lectin H (Siglec-H) inhibits Th cell and Ab responses in the presence of strong immune stimulation in an Ag-specific manner. Correlating with sustained low-level MHC class II-restricted Ag presentation on PDCs, Siglec-H-mediated Ag delivery induced a hyporesponsive state in CD4(+) T cells leading to reduced expansion and Th1/Th17 cell polarization without conversion to Foxp3(+) regulatory T cells or deviation to Th2 or Tr1 cells. Siglec-H-mediated delivery of a T cell epitope derived from the autoantigen myelin oligodendrocyte glycoprotein to PDCs effectively delayed onset and reduced disease severity in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis by interfering with the priming phase without promoting the generation or expansion of myelin oligodendrocyte glycoprotein-specific Foxp3(+) regulatory T cells. We conclude that Ag delivery to PDCs can be harnessed to inhibit Ag-specific immune responses and prevent Th cell-dependent autoimmunity.

• Cytokines and effector T cell subsets causing autoimmune CNS disease.

  Authors: Franziska Petermann, Thomas Korn

  FEBS letters. 04/2011; 585(23):3747-57.

  Although experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has beenAlthough experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has been successfully used to prove that MS like autoimmunity in the CNS is orchestrated by autoantigen specific T cells. EAE was also very useful to refute the idea that IFN-γ producing T helper type 1 (Th1) cells were the sole players within the pathogenic T cell response. Rather, "new" T cell lineages such as IL-17 producing Th17 cells or IL-9 producing Th9 cells have been first discovered in the context of EAE. Here, we will summarize new concepts of early and late T cell plasticity and the cytokine network that shapes T helper cell responses and lesion development in CNS specific autoimmunity.

• Report on the 2nd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010.

  Authors: Tim Magnus, Ralf A Linker, Sven G Meuth, Christoph Kleinschnitz, Thomas Korn

  Experimental & translational stroke medicine. 04/2011; 3(1):3.

  ABSTRACT: Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration.

• TNF-alpha-dependent loss of IKKbeta-deficient myeloid progenitors triggers a cytokine loop culminating in granulocytosis.

  Authors: Arun K Mankan, Ozge Canli, Sarah Schwitalla, Paul Ziegler, Jurg Tschopp, Thomas Korn, Florian R Greten

  Proceedings of the National Academy of Sciences of the United States of America. 04/2011; 108(16):6567-72.

  Loss of IκB kinase (IKK) β-dependent NF-κB signaling in hematopoietic cells is associated with increased granulopoiesis. Here we identify a regulatory cytokine loop that causes neutrophilia inLoss of IκB kinase (IKK) β-dependent NF-κB signaling in hematopoietic cells is associated with increased granulopoiesis. Here we identify a regulatory cytokine loop that causes neutrophilia in Ikkβ-deficient mice. TNF-α-dependent apoptosis of myeloid progenitor cells leads to the release of IL-1β, which promotes Th17 polarization of peripheral CD4(+) T cells. Although the elevation of IL-17 and the consecutive induction of granulocyte colony-stimulating factor compensate for the loss of myeloid progenitor cells, the facilitated induction of Th17 cells renders Ikkβ-deficient animals more susceptible to the development of experimental autoimmune encephalitis. These results unravel so far unanticipated direct and indirect functions for IKKβ in myeloid progenitor survival and maintenance of innate and Th17 immunity and raise concerns about long-term IKKβ inhibition in IL-17-mediated diseases.

• Immune mechanisms of new therapeutic strategies in MS: teriflunomide.

  Authors: Malte C Claussen, Thomas Korn

  Clinical immunology (Orlando, Fla.). 02/2011; 142(1):49-56.

  At present, a series of oral disease-modifying agents is being introduced for the treatment of multiple sclerosis. With the exception of laquinimod, the "new" oral compounds have already beenAt present, a series of oral disease-modifying agents is being introduced for the treatment of multiple sclerosis. With the exception of laquinimod, the "new" oral compounds have already been approved for other indications such as organ transplantation (FTY720), psoriasis (dimethylfumarate), hairy cell leukemia (cladribine), and rheumatoid arthritis (leflunomide). Leflunomide is the prodrug of teriflunomide which is the latest compound that has successfully been tested in a large phase III clinical trial in relapsing MS. Due to its favorable safety profile and its efficacy in rheumatoid arthritis where the aberrant immune response is in various aspects similar to the autoimmune reaction in MS patients, teriflunomide is a promising treatment option for MS patients. Here, we review the most important cell biological and immunological modes of action of teriflunomide, report on the available data on its pharmacokinetics in humans, and summarize the recent clinical trials of teriflunomide in relapsing MS.

• Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica.

  Authors: Sudhakar Reddy Kalluri, Veit Rothhammer, Ori Staszewski, Rajneesh Srivastava, Franziska Petermann, Marco Prinz, Bernhard Hemmer, Thomas Korn

  PloS one. 01/2011; 6(1):e16083.

  Antibodies to the water channel protein aquaporin-4 (AQP4), which is expressed in astrocytic endfeet at the blood brain barrier, have been identified in the serum of Neuromyelitis optica (NMO)Antibodies to the water channel protein aquaporin-4 (AQP4), which is expressed in astrocytic endfeet at the blood brain barrier, have been identified in the serum of Neuromyelitis optica (NMO) patients and are believed to induce damage to astrocytes. However, AQP4 specific T helper cell responses that are required for the generation of anti-AQP4 antibodies and most likely also for the formation of intraparenchymal CNS lesions have not been characterized. Using overlapping 15-meric peptides of AQP4, we identified the immunogenic T cell epitopes of AQP4 that are restricted to murine major histocompatibility complex (MHC) I-A(b). The N-terminal region of AQP4 was highly immunogenic. More precisely, the intracellular epitope AQP4(22-36) was detected as major immunogenic determinant. AQP4(82-108) (located in the second transmembrane domain), AQP4(139-153) (located in the second extracellular loop), AQP4(211-225) (located in the fifth transmembrane domain), AQP4(235-249) (located in the sixth transmembrane domain), as well as AQP4(289-306) in the intracellular C-terminal region were also immunogenic epitopes. AQP4(22-36) and AQP4(289-303) specific T cells were present in the natural T cell repertoire of wild type C57BL/6 mice and T cell lines were raised. However, active immunization with these AQP4 peptides did not induce signs of spinal cord disease. Rather, sensitization with AQP4 peptides resulted in production of IFN-γ, but also IL-5 and IL-10 by antigen-specific T cells. Consistent with this cytokine profile, the AQP4 specific antibody response upon immunization with full length AQP4 included IgG1 and IgG2, which are associated with a mixed Th2/Th1 T cell response. AQP4 is able to induce an autoreactive T cell response. The identification of I-A(b) restricted AQP4 specific T cell epitopes will allow us to investigate how AQP4 specific autoimmune reactions are regulated and to establish faithful mouse models of NMO that include both cellular and humoral responses against AQP4.

• Expression of miRNAs miR-133b and miR-206 in the Il17a/f locus is co-regulated with IL-17 production in αβ and γδ T cells.

  Authors: Jan D Haas, Kiran Nistala, Franziska Petermann, Namita Saran, Vijaykumar Chennupati, Susanne Schmitz, Thomas Korn, Lucy R Wedderburn, Reinhold Förster, Andreas Krueger, Immo Prinz

  PloS one. 01/2011; 6(5):e20171.

  Differentiation of T helper 17 cells (Th17) is a multistep process that involves the cytokines IL-6, TGF-β, and IL-23 as well as IL-1β, IL-21, and TNF-α. Thereby, robust induction of the capacity toDifferentiation of T helper 17 cells (Th17) is a multistep process that involves the cytokines IL-6, TGF-β, and IL-23 as well as IL-1β, IL-21, and TNF-α. Thereby, robust induction of the capacity to produce IL-17 involves epigenetic modifications of the syntenic Il17a/f locus. Using inbred mouse strains, we identified co-regulation of gene transcription at the Il17a/f locus with the nearby microRNAs miR-133b and miR-206 that are clustered approximately 45 kb upstream of Il17a/f. Expression of these microRNAs was specific for Th17 as compared to other CD4(+) T cell subsets and this was equally valid for in vitro polarized and ex vivo derived cells. From all factors analyzed, IL-23 was the most important cytokine for the in vitro induction of miR-133b and miR-206 in naive CD4(+) T cells of wild type mice. However, analysis of IL-23R deficient mice revealed that IL-23R signaling was not essential for the induction of miR-133b and miR-206. Importantly, we found a similar co-regulation in CCR6(+) and other γδ T cell subsets that are predisposed to production of IL-17. Taken together, we discovered a novel feature of T cell differentiation towards an IL-17-producing phenotype that is shared between αβ and γδ T cells. Notably, the specific co-regulation of miR-133b and miR-206 with the Il17a/f locus also extended to human Th17 cells. This qualifies expression of miR-133b and miR-206 in T cells as novel biomarkers for Th17-type immune reactions.

• How T cells take developmental decisions by using the aryl hydrocarbon receptor to sense the environment.

  Authors: Thomas Korn

  Proceedings of the National Academy of Sciences of the United States of America. 11/2010; 107(48):20597-8.

• Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system.

  Authors: Patrick Vollmar, Jennifer S Kullmann, Barbara Thilo, Malte C Claussen, Veit Rothhammer, Hortenzia Jacobi, Johann Sellner, Stefan Nessler, Thomas Korn, Bernhard Hemmer

  Journal of immunology (Baltimore, Md. : 1950). 10/2010; 185(10):6338-47.

  Active immunization with amyloid-β (Aβ) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, thisActive immunization with amyloid-β (Aβ) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aβ(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Aβ(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aβ(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aβ(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aβ(1-42)/CFA. Thus, this study identifies adjuvant effects of Aβ(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.

• γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

  Authors: Franziska Petermann, Veit Rothhammer, Malte C Claussen, Jan D Haas, Lorena Riol Blanco, Sylvia Heink, Immo Prinz, Bernhard Hemmer, Vijay K Kuchroo, Mohamed Oukka, Thomas Korn

  Immunity. 09/2010; 33(3):351-63.

  Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of γδ T cells expresses the IL-23Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of γδ T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that γδ T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although γδ T cells produced Th17 cell-associated cytokines in response to IL-23, their major function was to prevent the development of regulatory T (Treg) cell responses. IL-23-activated γδ T cells rendered αβ effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cells into Foxp3(+) Treg cells in vivo. Thus, IL-23, which by itself has no direct effect on Treg cells, is able to disarm Treg cell responses and promote antigen-specific effector T cell responses via activating γδ T cells.

• Proinflammatory T helper type 17 cells are effective B-cell helpers.

  Authors: Meike Mitsdoerffer, Youjin Lee, Anneli Jäger, Hye-Jung Kim, Thomas Korn, Jay K Kolls, Harvey Cantor, Estelle Bettelli, Vijay K Kuchroo

  Proceedings of the National Academy of Sciences of the United States of America. 08/2010; 107(32):14292-7.

  T helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells haveT helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells have been associated with a number of autoimmune diseases. However, it is not clear whether TH17 cells can also serve as effective helper cells. Here we show that TH17 cells can function as B-cell helpers in that they not only induce a strong proliferative response of B cells in vitro but also trigger antibody production with class switch recombination in vivo. Transfer of TH17 cells into WT or T-cell receptor alpha-deficient mice, which lack endogenous T cells, induces a pronounced antibody response with preferential isotype class switching to IgG1, IgG2a, IgG2b, and IgG3, as well as the formation of germinal centers. Conversely, blockade of IL-17 signaling results in a significant reduction in both number and size of germinal centers. Whereas IL-21 is known to help B cells, IL-17 on its own drives B cells to undergo preferential isotype class switching to IgG2a and IgG3 subtypes. These observations provide insights into the unappreciated role of TH17 cells and their signature cytokines in mediating B-cell differentiation and class switch recombination.

• Report on the 1st scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009.

  Authors: Tim Magnus, Ralf Linker, Sven G Meuth, Christoph Kleinschnitz, Thomas Korn

  Experimental & translational stroke medicine. 03/2010; 2:7.

  Report on the 1st scientific meeting of the "Verein zur Forderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st,Report on the 1st scientific meeting of the "Verein zur Forderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009. A scientific meeting report.

• Interleukin-17 and type 17 helper T cells.

  Authors: Pierre Miossec, Thomas Korn, Vijay K Kuchroo

  The New England journal of medicine. 09/2009; 361(9):888-98.

• Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells.

  Authors: Amit Awasthi, Lorena Riol-Blanco, Anneli Jäger, Thomas Korn, Caroline Pot, George Galileos, Estelle Bettelli, Vijay K Kuchroo, Mohamed Oukka

  Journal of immunology (Baltimore, Md. : 1950). 06/2009; 182(10):5904-8.

  IL-23, an IL-12 family member, has been implicated in the development of Th17 cells and the progression of autoimmune diseases. However, due to the lack of availability of sensitive Ab reagentsIL-23, an IL-12 family member, has been implicated in the development of Th17 cells and the progression of autoimmune diseases. However, due to the lack of availability of sensitive Ab reagents specific for the IL-23 receptor (IL-23R), it has been difficult to characterize the cell types that express the IL-23R and are responsive to IL-23 in vivo. To address the role of IL-23 in vivo, we have generated a novel "knock-in" mouse in which we have replaced the intracellular domain of the IL-23R with the GFP. We show that in addition to Th17 cells, a subset of myeloid cells express IL-23R and respond to IL-23 by producing IL-17 and IL-22. Our studies further demonstrate that IL-23R expression is crucial for generation of encephalitogenic Th17 cells, but its expression on the innate immune system is dispensible in the development of experimental autoimmune encephalomyelitis.

• IL-17 and Th17 Cells.

  Authors: Thomas Korn, Estelle Bettelli, Mohamed Oukka, Vijay K Kuchroo

  Annual review of immunology. 02/2009;

  CD4(+) T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided intoCD4(+) T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-beta plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORgammat, and RORalpha) involved in the development of Th17 cells have just been identified. The participation of TGF-beta in the differentiation of Th17 cells places the Th17 lineage in close relationship with CD4(+)CD25(+)Foxp3(+) regulatory Tcells (Tregs), as TGF-beta also induces differentiation of naive Tcells into Foxp3(+) Tregs in the peripheral immune compartment. The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding Tcell differentiation. Furthermore, we now appreciate the importance of Th17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease. Expected final online publication date for the Annual Review of Immunology Volume 27 is March 19, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

• Immunological Basis for the Development of Tissue Inflammation and Organ-Specific Autoimmunity in Animal Models of Multiple Sclerosis.

  Authors: Thomas Korn, Meike Mitsdoerffer, Vijay Kuchroo

  Results and problems in cell differentiation. 02/2009;

  Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) that has shaped our understanding of autoimmune tissue inflammation in the central nervous system (CNS).Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) that has shaped our understanding of autoimmune tissue inflammation in the central nervous system (CNS). Major therapeutic approaches to MS have been first validated in EAE. Nevertheless, EAE in all its modifications is not able to recapitulate the full range of clinical and histopathogenic aspects of MS. Furthermore, autoimmune reactions in EAE-prone rodent strains and MS patients may differ in terms of the relative involvement of various subsets of immune cells. However, the role of specific molecules that play a role in skewing the immune response towards pathogenic autoreactivity is very similar in mice and humans. Thus, in this chapter, we will focus on the identification of a novel subset of inflammatory T cells, called Th17 cells, in EAE and their interplay with other immune cells including protective regulatory T cells (T-regs). It is likely that the discovery of Th17 cells and their relationship with T-regs will change our understanding of organ-specific autoimmune diseases in the years to come.