Infektionsimmunologie > AG Tolosa
Group leader: Eva Tolosa
Group members: Verena Brucklacher-Waldert, Angélica Cuapio, Denise Orozco, Anne Schramm, Vivien Thom
Research Projects
Effector cell subsets: Th1 and Th17 cells
The differentiation of naïve CD4 T cells into different lineages drives immune responses to pathogens, or to self antigens, in the case of autoimmunity. Recent data suggest that a model involving exclusively IFN-g-producing Th1 and IL-4-producing Th2 cells might be too simplistic and demonstrate that IL-17-producing CD4+ cells, or Th17 cells, play a significant role in the inflammatory response to certain pathogens and in autoimmunity. The role of Th17 cells in human autoimmune disease, however, remains to be elucidated, and the lack of a surface marker has hampered research on this new T helper subset.
We have shown that IL-17 is expressed at the cell surface and constitutes a reliable marker for the identification, isolation and analysis of human and murine Th17 cells. Cells expressing IL-17A express RORgt, the canonical transcription factor of Th17 cells, IL-23R, and produce large amounts of IL-17A upon stimulation. We used this marker to isolate and expand Th17 cells from peripheral blood and cerebrospinal fluid from multiple sclerosis patients and to raise T cell clones for further analysis. While Th1 clones keep producing exclusively IFN-g under different culture conditions, Th17, and especially Th1/17 clones (producing simultaneously IFN-g and IL-17A) show a certain degree of plasticity to the cytokine milieu in their environment.
Regarding the role of Th17 cells in multiple sclerosis, we have analyzed the frequency and the phenotype of these cells in the cerebrospinal fluid and peripheral blood of patients. The frequency of Th17 cells was higher in the cerebrospinal fluid of patients, especially during acute episodes, while Th1 cells remained at similar levels. A thorough analysis of human T cell clones and ex vivo T cells revealed that Th17 cells express higher basal levels of activation markers, costimulatory molecules and adhesion molecules than Th1 cells, and functional assays revealed that Th17 cells bind better to human endothelial cells, proliferate more readily, are less susceptible to regulatory T cell-mediated suppression than Th1 cells, altogether suggestion a high pathogenic potential.
Our research focuses on finding the features that make Th17 cells pathogenic in autoimmune disease and exploring the plasticity of these subsets to the environment. We are also interested in the putative thymic origin of Th17 cells, and their relationship with regulatory T cells.
Regulatory cells
Regulatory cells are in charge of maintaining tolerance to self proteins and a homeostatic balance with the obligate flora, and also in preventing excessive immune responses to pathogens. CD4+ CD25+ FOXP3+ T regulatory (Treg) cells are the best characterized subset, and their role in preventing autoimmune disease is well documented.
Leukocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury in an animal model for stroke, but the roles of specific lymphocyte subpopulations and cytokines during stroke are still obscure. IL-23 and IL-17 as well as gamma delta T cells have recently been shown to play a detrimental role in, while Treg had a regulatory immune effect on disease progression. In cooperation with the Experimental Research in Stroke and Inflammation (ESRI) research group, we plan to evaluate the relation between damage and immune regulation exerted by different leukocyte subsets and inflammatory cytokines in ischemia-induced inflammation, extending current knowledge from animal models to human disease.
In addition to Treg, other lymphocytes subsets, amongst them a special subset of NK cells, the CD56bright, are known to have immunoregulatory properties. Anti-IL-2Rα (CD25) therapy constitutes a novel immunomodulatory treatment for multiple sclerosis patients that do not respond to conventional therapy. A marked increase in the number of CD56 bright NK cells is observed few weeks after drug administration, correlating with a reduction in brain inflammation and improvement of the clinical symptoms in most patients. We are currently analyzing the dynamics of NK cell subsets in anti-CD25-treated multiple sclerosis patients, and by means of in vitro studies try to find the mechanism for the expansion of this regulatory subset.
Selected publications:
Immune regulation
Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Th17 cells display high pathogenic potential and are increased in the CSF of multiple sclerosis patients during relapse. Brain 2009 (in press)
Brucklacher-Waldert V, Steinbach K, Kolster M, Lioznov M, Hoelscher C, Tolosa E. Phenotypical and functional characterization of human Th17 cells unambiguously identified by surface IL-17A expression. J Immunol. 2009; 183:5494-501.
Luther C, Stoeckle C*, Adamopoulou*, Brucklacher-Waldert V, Rosenkranz D, Stoltze L, Lauer S, Poeschel S, Melms A, Tolosa E. Prednisolone treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis patients. J Immunol 2009; 183:841-848
Gelderblom M*, Leypoldt F*, Steinbach K*, Behrens D, Choe CU, Siler D, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009 40(5):1849-1857
Feger U*, Tolosa E*, Yu-Hwa H*, Biedermann T, Melms A, Wiendl H. HLA-G expression defines a novel regulatory T cell subset present in human peripheral blood and sites of neuroinflammation. Blood 2007; 110:568-577
Feger U, Luther C, Schreiner B, Pöschel S, Melms A, Tolosa E*, Wiendl H*. The frequency of CD4+CD25+ T regulatory cells is increased in the CSF but not in the blood of MS patients. Clin exp Immunol 2007;147:412-418.
Luther C, Poeschel S, Varga M, Melms A, Tolosa E. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J Neuroimmunol 2005;164:124-128
Tolosa E, Ashwell JD. Thymus-derived glucocorticoids and the regulation of antigen-specific T- cell development. Neuroimmunomodulation 1999;6:90-96
Tolosa E, King LB, Ashwell JD. Thymocyte glucocorticoid resistance alters positive selection and inhibits autoimmunity and lymphoproliferative disease in MRL-lpr/lpr mice. Immunity 1998;8:67-76
Antigen processing and presentation
Stoeckle C, Tolosa E. Antigen processing and presentation in MS. In: "Molecular Basis of MS -Research Trends. Part I: The immune system”. Springer
Stoeckle C, Gouttefangeas C, Hammer M, Weber E, Melms A, Tolosa E. Cathepsin W, expressed exclusively in CD8+ and NK cells, is secreted during target cell killing but is not essential for cytotoxicity in human CTLs. Exp Hematol. 2009; 37(2):266-75.
Viken MK, Sollid HD, Joner G, Dahl-Jørgensen K, Rønningen KS, Undlien DE, Flatø B, Selvaag AM, Førre Ø, Kvien TK, Thorsby E, Melms A, Tolosa E, Lie BA.Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and early-onset myasthenia gravis. Human Immunol 2007; 68:748-755
Melms A, Luther C, Stoeckle C, Poeschel S, Schroth P, Varga M, Winehold W, Tolosa E. Thymus and myasthenia gravis: antigen processing in the human thymus and the consequences for the generation of autoreactive T cells. Acta Neurol Scand Suppl. 2006;183:12-13
Burster T, Beck A, Tolosa E, Schnorrer P, Reich M, Krauss M, Kalbacher H, Häring HU, Weber E, Overkleeft H, Driessen C. Differential processing of an autoantigen in lysosomes from human monocyte-derived and peripheral blood dendritic cells. J Immunol 2005;175:5940-5949
Stoeckle C, Burster T, Gnau V, Driessen C, Kalbacher H, Melms A, Tolosa E. Processing of MBP by human thymic and peripheral antigen presenting cells. Is processing regulated in patients with multiple sclerosis? In: Editore M, ed. Immunology 2004. Vol. 3.
Burster T, Beck A, Tolosa E, Marin-Esteban V, Rotzschke O, Falk K, Lautwein A, Reich M, et al. Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J Immunol 2004;172:5495-5503
Tolosa E, Li W, Yasuda Y, Wienhold W, Denzin LK, Lautwein A, Driessen C, Schnorrer P, Weber E, Stevanovic S, Kurek R, Melms A, Bromme D. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 2003;112:517-526
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