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The Journal of Immunology, 2000, 165: 4994-5003.
Copyright © 2000 by The American Association of Immunologists

Dendritic Cells Prime In Vivo Alloreactive CD4 T Lymphocytes Toward Type 2 Cytokine- and TGF-ß-Producing Cells in the Absence of CD8 T Cell Activation1

Gilles Foucras2, Jérôme D. Coudert2, Christiane Coureau and Jean-Charles Guéry3

Institut National de la Santé et de la Recherche Médicale Unité 28, Institut Fédératif de Recherche 30, Hôpital Purpan, Toulouse, France

The mechanisms that influence the polarization of CD4 T cells specific for allogeneic MHC class II molecules in vivo are still poorly understood. We have examined the pathway of alloreactive CD4 T cell differentiation in a situation in which only CD4 T cells could be activated in vivo. In this report we show that priming of adult mice with allogeneic APC, in the absence of MHC class I-T cell interactions, induces a strong expansion of type 2 cytokine-producing allohelper T cells. These alloantigen-specific CD4 T cells directly recognize native allogeneic MHC class II molecules on APC and secrete, in addition to the prototypic Th2 cytokines IL-4, IL-5, and IL-10, large amounts of TGF-ß. The default Th2-phenotype acquisition is not genetically controlled and occurred both in BALB/c and C57BL/6 mice. CD8 T cells are the principal cell type that controls CD4 T cell differentiation in vivo. Furthermore, we demonstrate that strong Th2 priming can be induced not only with allogeneic splenocytes but also with a low number of bone marrow-derived dendritic cells. Finally, using a passive transfer system, we provide direct evidence that CD8 T cell expansion in situ promotes alloreactive Th1 cell development principally by preventing their default development to the Th2 pathway in a mechanism that is largely IFN-{gamma} independent. Therefore, this work demonstrates that type 2 cytokine production represents a dominant pathway of alloreactive CD4 T cell differentiation in adult mice, a phenomenon that was initially thought to occur only during the neonatal period.




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