Dendritic cells prime in vivo alloreactive CD4 T lymphocytes toward type 2 cytokine- and TGF-beta-producing cells in the absence of CD8 T cell activation.
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-beta. 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.
Foucras
G
G
Institut National de la Santé et de la Recherche Médicale Unité 28, Institut Fédératif de Recherche 30, Hôpital Purpan, Toulouse, France.
Coudert
J D
JD
Coureau
C
C
Guéry
J C
JC
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D007114:Immunization; D007279:Injections, Subcutaneous; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007519:Isoantigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D007519:Isoantigens; D016212:Transforming Growth Factor beta; D001613:beta 2-Microglobulin; D015847:Interleukin-4