Back, J.

Birchmeier, W.

Duboux, S.

Gardiol, N.

Held, W.

Huelsken, J.

Jeannet, G.

Kuttler, F.

Leutz, A.

Malanchi, I.

Scarpellino, L.

Scheller, M.

Infoscience - École polytechnique fédérale de Lausanne

S W I S S  M E D  W K L Y 2 0 0 8 ; 1 3 8 ( S u p p l  1 6 3 )  ·  w w w . s m w . c h13 S  !""#$%&&'()*+,)%(-#.#/ 0012#3#041270Canonical Wnt signalling is required for thymus organogenesisS. Zuklys1, T. Barthlott1, J. Gill1, M. Keller1, S. Zhanybekova1, M. Hauri1, K-J. Na1, K. Hafen1, E. Illingworth2, A. Moon3, Y. Hamazaki4, G. Holländer1.1 University Children’s Hospital of both Cantons of Basel (Basel, CH);2 University System Health Science Center (Huston, USA); 3 University of Utah School of Medicine (Salt Lake City, USA); 4 Kyoto University (Sakyo-ku,JP)The thymus achieves two interrelated functions essential for theadaptive immune system; the life-long generation of new T cells andthe selection of a repertoire of T cells tolerant to self-antigens butreactive to foreign peptides. Thymus organogenesis is initiated in themouse at embryonic day 10.5 when endodermal cells of the thirdpharyngeal pouch become committed to a thymus fate. Theformation of an epithelial primordium and the subsequentdifferentiation of thymic epithelial cells (TEC) into distinctsubpopulations constitute the necessary prerequisite for theformation of a thymic microenvironment proficient to support T celldevelopment. However, the precise molecular signals that dictateTEC fate commitment and differentiation remain largely unknown.Wnt signaling has, however, been implicated in thymusorganogenesis Here we demonstrate that thymus organogenesis isdifferentially affected depending on the timing of the loss in canonicalWnt signalling. Deletion of canonical Wnt signalling duringdevelopmental stages prior to the formation of a thymus anlagecauses thymic agenesis. In contrast, loss of canonical Wnt signallingat a later stage does not preclude the formation of a regularlystructured and composed thymic microenvironment but leads tothymic hypoplasia despite normal T cell development. Taken together,these results demonstrate an essential role for canonical Wntsignaling during early stages of thymus organogenesis whereasactivation through the same pathway determines thymus cellularityduring later stages and organ maintenance of the thymus.71Mature Aire+ mTEC development is controlled by antigen-specific TCR-MHC class II mediated interactions withautoreactive CD4+ thymocytesM. Irla1, S. Hugues1, J. Gill2, G. Holländer2, W. Reith1. 1 Centre Médical Universitaire (Genève, CH); 2 University Children’s Hospital (Basel, CH)Medullary thymic epithelial cells (mTEC) are specialized for inducingcentral immunological tolerance to self-antigens. To accomplish this,mTEC must adopt a mature phenotype characterized by expressionof the autoimmune regulator Aire, which activates the transcription ofnumerous genes encoding tissue-restricted self-antigens. Themechanisms that direct mTEC maturation are poorly understood. Wehave discovered that the number of mature mTEC is controlled in thepostnatal thymus by direct physical interactions between CD4+thymocytes bearing autoantigen-specific TCR and mTEC displayingthe cognate self-peptide/MHC class II complexes. The competenceof CD4+ thymocytes for this process is imparted by their expressionof CD40L, which delivers an essential signal upon binding to CD40Lon mTEC. This crosstalk between CD4+ thymocytes and mTECdefines a novel checkpoint pivotal for thymic stromal and lymphoiddevelopment because it generates a mature mTEC populationcompetent for ensuring central T cell tolerance.number within the lesions did not differ significantly within theinfected groups, however, parasite metastasis was observed only incontrol groups but not in the Notch-/- groups. Fourteen weeks afterinfection with L. mexicana, control+/+ mice developed significantlevels of L. mexicana-specific IgG1 and IgE antibodies indicating ofthe development of a Th2 immune response. In contrast, infection ofN1-/- mice resulted in a decreased production of parasite-specificIgG1 and IgE in the serum, with corresponding increase in Th1-specific IgG2a antibodies. This decrease in Th2 antibodies with thecorresponding increase in IgG2a antibodies was even more drasticwhen CD4+ T cells lacked both Notch1 and Notch2 (N1-/-N2-/-mice). In contrast, L. mexicana-infected N2-/- mice had similar levelsof IgG1 and IgE as controls littermates but the secretion of IL-4 andIL-10 by CD4+ T cells was significantly enhanced while the secretionof IFN-g was decreased, suggesting a role of Notch2 in Th1differentiation. Taken together, these results reveal that the IL-4produced by CD4+ T cells is not essential for lesion developmentfollowing infection with L. mexicana, but is involved in parasitemetastasis. In this model of infection, Notch1 contributes to Th2differentiation while Notch2 appears to be involved in Th1 responseand both Notch1 and Notch2 seems to regulate each other.73T-cell development occurs in the combined absence of thecanonical Wnt signal-transducers beta- and gamma-cateninG. Jeannet1, M. Scheller2, L. Scarpellino1, S. Duboux3, N. Gardiol1, J. Back1, F. Kuttler3, I. Malanchi3, W. Birchmeier2, A. Leutz2, J. Huelsken3, W. Held1. 1 LICR (Epalinges, CH); 2 Max-Delbrück Center for MolecularMedicine (Berlin, D); 3 EPFL (Epalinges, CH)The canonical Wnt signaling pathway plays key roles in stem cellmaintenance, expansion of committed progenitor cells and control oflineage decisions in a variety of tissues including the hematopoieticsystem. Beta-catenin is the central molecule in the canonical Wntsignaling pathway. Beta catenin transmits Wnt signals into thenucleus, where it acts as transcriptional co-activator by binding tomembers of the LEF/TCF (Lymphoid enhancer factor/T cell factor)family of transcription factors. The related molecule gamma catenin(plakoglobin) can fulfill similar functions to activate target genes uponWnt signaling.Gene ablation of TCF-1 impaired T cell development. TCF-1deficiency resulted in incomplete blocks within the CD4-8- thymocytecompartment and at the transition from immature single positive tothe CD4+8+ stage. Strikingly, a genetic complementation approachshowed that the N-terminal domain of TCF-1 was essential to rescuethymocyte development in TCF-1 deficient mice. This domain in TCF-1 includes a beta catenin binding site. We show that this domain alsocontains a gamma catenin interaction site, suggesting that cateninbinding to TCF-1 is critical for T cell development. However, resultsobtained by individual gene ablations of the two known signaltransmitters beta- and gamma catenin did not recapitulate thephenotype of TCF-1-deficient mice.Based on this discrepancy we analyzed thymopoiesis in thecombined absence of both, beta- and gamma catenin. Unexpectedly,we find that T cell development occurs normally in the combinedabsence of the two known Wnt signal transmitters beta- and gammacatenin. We performed reporter assays to address whether canonicalWnt signaling was not needed for thymocyte development or whethersuch signals were transduced in the absence of beta- and gammacatenin. We find that beta- and gamma catenin-deficient thymocytesand peripheral T cells retain a significant capacity to transducecanonical Wnt signals. These data suggest a novel mechanism ofTCF-1/Wnt signal transduction in the hematopoietic system.72Role of Notch1 and Notch2 receptors in CD4+ T helperdifferentiationF. Auderset1, M. Charmoy1, F. Desgranges1, P. Launois1, F. Radtke2,F. Tacchini-Cottier1. 1 University of Lausanne (Epalinges, CH); 2 Ecole Polytechnique Fédérale de Lausanne (Epalinges, CH)Notch proteins are evolutionary conserved receptors involved in celldifferentiation and development processes, especially in binary cellfate decisions. The role of the Notch pathway in T helper (Th)differentiation remains controversial. In order to characterize the roleof Notch1 and Notch2 in CD4+ Th differentiation, we used mice witha T cell-specific ablation of the Notch1 (N1-/-), Notch2 (N2-/-) or bothNotch1 and Notch2 (N1-/-N2-/-) and infected them with Leishmaniamexicana, which induces IL-4-dependent cutaneous leishmaniasisand Th2 differentiation when injected in the back rump. Evolution oflesions and of the immune response was compared to that of theircontrol littermates (+/+). Lesion development as well as parasite74Interleukin-7-driven networking in normal and ectopic lymphoidorgan developmentS. Schmutz1, N. Bosco1, H. Acha-Orbea2, A. Rolink1, R. Ceredig3, D. Finke1. 1 Department of Biomedicine (Basel, CH); 2 Department ofBiochemistry (Lausanne, CH); 3 INSERM U645 (Besançon, F)Antimicrobial adaptive immune responses are generated in secondarylymphoid organs such as spleen, lymph nodes (LNs) and Peyer’spatches (PPs). In addition, inducible ectopic lymphoid tissues form ininflammatory lesions of chronic infections, autoimmune diseases,allergic reactions and chronic graft rejection. These so-called “tertiarylymphoid tissues” can function as inductive sites for adaptive immuneresponses against self and non-self antigens. During embryogenesis,

T-cell development occurs in the combined absence of the canonical Wnt signal-transducers beta- and gamma-catenin

http://infoscience.epfl.ch/record/157752/files/Swiss-Medical-Weekly-Suppl-163_Huelsken.pdf

T-cell development occurs in the combined absence of the canonical Wnt signal-transducers beta- and gamma-catenin

Abstract

Similar works

Full text

Available Versions

Infoscience - École polytechnique fédérale de Lausanne