Unlike T cells that, once activated in the lymph node through interactions with dendritic cells, proliferate and leave the lymph node, mature dendritic cells undergo apoptosis. However, T cell activation requires several hours of contacts with dendritic cells, so Riol-Blanco et al. investigated whether dendritic cells engaging in T cell contact through the formation of an immune synapse had a survival advantage relative to single dendritic cells. Riol-Blanco et al. noted that, in culture, human dendritic cells were particularly prone to undergo apoptosis when placed in serum-free medium, whereas T cells were relatively resistant to apoptosis under these same conditions. The addition of T cells and the forced interaction of the dendritic cells with the T cells through a centrifugation method increased the percentage of dendritic cells that survived in serum-free medium. Physical contact was required because separation of the T cells from the dendritic cells with a porous membrane failed to promote survival. With two-photon microscopy and a fluorescent label for active caspases, the authors showed that a higher percentage of single dendritic cells (those that were not engaged in immune synapse formation) in mouse lymph nodes were positive for active caspases than were dendritic cells engaged in an immune synapse with T cells. Dendritic cells in culture that were forced to form immune synapses with human T cells exhibited intense phosphorylated tyrosine staining, staining for phosphorylated Akt1, and recruitment of an indicator molecule for phosphatidylinositol 3,4,5-trisphosphate [the product of phosphoinositide 3-kinase (PI3K)] in the region of the immune synapse. Treatment of the dendritic cell–T cell conjugates with an inhibitor of PI3K did not prevent immune synapse formation, but did eliminate Akt1 activation, and only partially inhibited dendritic cell survival. Dendritic cells expressing a tagged form of a subunit of nuclear factor κB (NF-κB) showed that this protein appeared with a higher frequency in the nucleus of cells forming an immune synapse relative to single dendritic cells. Knockdown of the Forkhead box class O family member FOXO1 in dendritic cells decreased apoptosis of these cells in serum-free medium, and immune synapse formation triggered the translocation of FOXO1 from the nucleus to the cytosol. Clustering of CD40, but not the integrin LFA-1, on the dendritic cells activated Akt1. The authors propose that when dendritic cells form an immune synapse with a T cell, they receive a survival signal through the CD40 receptor that activates Akt1, which activates the prosurvival transcription factor NF-κB and inhibits the proapoptotic transcription factor FOXO1.
L. Riol-Blanco, C. Delgado-Martín, N. Sánchez-Sánchez, L. M. Alonso-C, M. D. Gutiérrez-López, G. M. del Hoyo, J. Navarro, F. Sánchez-Madrid, C. Cabañas, P. Sánchez-Mateos, J. L. Rodríguez-Fernández, Immunological synapse formation inhibits, via NF-κB and FOXO1, the apoptosis of dendritic cells. Nat. Immunol. 10, 753–760 (2009). [PubMed]