Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling.
The Hedgehog (Hh) family of signaling molecules functions in the development of numerous tissues during embryogenesis and has also been involved in adult self-renewing tissues. Recent results have demonstrated that the different components of the Hh signaling pathway are expressed in the human thymus. In this study, we investigate whether thymic dendritic cells (DCs) are cell targets for Hh signaling. Both components of the Hh receptor, Patched and Smoothened, as well as other Hh-binding proteins with modulating functions, are expressed by human thymic DCs. The expression of Gli1, Gli2, and Gli3 transcription factors suggests that the Hh signaling pathway is active in thymic DCs, and approximately one-half of thymic DCs produces Sonic Hh (Shh). The culture of thymic DCs with Shh protects them from apoptosis [similarly to CD40 ligand (CD40L)], and these antiapoptotic effects are related to an up-regulation of Bcl-2 and Bcl-X(L) protein expression. The addition of the Hh pathway inhibitor, cyclopamine, decreases DC viability and impairs their allostimulatory function in vitro. In addition, the blockade of the Hh signaling pathway by cyclopamine treatment abrogates the up-regulation of HLA-DR, CD86, CD80, and CD83 expression induced by CD40L on thymic DCs. Finally, we also show that after activation with CD40L thymic DCs down-regulate the expression of Hh receptor components as well as Shh production. Taken together, these results suggest that the survival and function of thymic DCs are regulated by an autocrine Hh signaling.
Varas
Alberto
A
Department of Cell Biology, Faculty of Medicine, Ciudad Universitaria, Complutense University, Madrid, Spain. avaras@bio.ucm.es
Hernández-López
Carmen
C
Valencia
Jaris
J
Mattavelli
Silvia
S
Martínez
Victor G
VG
Hidalgo
Laura
L
Gutiérrez-Frías
Cruz
C
Zapata
Agustín G
AG
Sacedón
Rosa
R
Vicente
Angeles
A
D019013:CD40 Antigens / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology*
D019013:CD40 Antigens; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface