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* Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée,
Institut National de la Santé et de la Recherche Médicale, Unité 631,
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6102, Marseille, France; and
Institut National de la Santé et de la Recherche Médicale Unité 563,
¶ Université Toulouse III Paul Sabatier, and
|| Centre Hospitalier de l’Université Purpan, Service d’Anatomie Pathologique, Toulouse, France
Mutant mice in which tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (LatY136F mice) develop a lymphoproliferative disorder involving polyclonal CD4 effector T cells that produce massive amounts of IL-4 and trigger severe Th2 inflammation. Naive CD4 T cells can themselves produce IL-4 and thereby initiate a self-reinforcing positive regulatory loop that involves the STAT6 transcription factor and leads to Th2 polarization. We determined the functional outcome that results when LatY136F T cells differentiate in the absence of such STAT6-dependent regulatory loop. The lack of STAT6 had no effect on the timing and magnitude of the lymphoproliferative disorder. However, in LatY136F mice deprived of STAT6, the expanding CD4 T cell population was dominated by Th1 effector cells that triggered B cell proliferation, elevated IgG2a and IgG2b levels as well as the production of autoantibodies. In contrast to LatY136F mice that showed no CD8 T cell expansion, the CD8 T cells present in LatY136F mice deprived of STAT6 massively expanded and acquired effector potential. Therefore, the lack of STAT6 is sufficient to convert the Th2 lymphoproliferative disorder that characterizes LatY136F mice into a lymphoproliferative disorder that is dominated by Th1 and CD8 effector T cells. The possibility to dispose of a pair of mice that differs by a single gene and develops in the absence of deliberate immunization large numbers of Th cells with almost reciprocal polarization should facilitate the identification of genes involved in the control of normal and pathological Th cell differentiation.
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1 This work was supported by Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, European Commision (MUGEN network of excellence (Grant LSHG-CT-2005-005203) and SYBILLA programme (Grant HEALTH-F4-2008-201106)), Fondation pour la Recherche Médicale, (Défis de la Recherche en Allergologie), and Project DC in vivo from Agence Nationale pour la Recherche. C.A. is supported by a Postdoctoral Fellowship from La Fondation pour la Recherche Médicale. M. Mingueneau is supported by a Doctoral Fellowship from Ecole Normale Supérieure.
2 Address correspondence and reprint requests to Dr. Bernard Malissen, Centre d’Immunologie de Marseille-Luminy, Campus de Luminy, Case 906, 13288 Marseille, Cedex 09, France. E-mail address: bernardm{at}ciml.univ-mrs.fr
3 Abbreviations used in this paper: LAT, linker for activation of T cell; WT, wild type.
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