Cdc42-mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the immune synapse.
The immune synapse (IS) forms as dendritic cells (DCs) and T cells interact in lymph nodes during initiation of adaptive immunity. Factors that contribute to the formation and maintenance of IS stability and function have been mostly studied in T cells, whereas little is known about events occurring during synapse formation in DCs. Here, we show that DCs activated by Toll-like receptor (TLR) agonists reorient the microtubule-organizing center (MTOC) toward the interacting T cell during antigen-specific synapse formation through a mechanism that depends on the Rho GTPase Cdc42. IL-12, a pivotal cytokine produced by DCs, is found enriched around the MTOC at early time points after TLR ligation and is dragged to the DC-T cell interface in antigen-specific synapses. Synaptic delivery of IL-12 induces activation of pSTAT4 and IFN-γ neosynthesis in CD8(+) naive T cells engaged in antigen-specific conjugates and promotes the survival of antigen-primed T cells. We propose that DC polarization increases the local concentration of proinflammatory mediators at the IS and that this represents a new mechanism by which T cell priming is controlled.
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149, Trieste, Italy.
Julian
J
Pulecio
Jelena
J
Petrovic
Francesca
F
Prete
Giulia
G
Chiaruttini
Ana-Maria
AM
Lennon-Dumenil
Chantal
C
Desdouets
Stephane
S
Gasman
Oscar R
OR
Burrone
Federica
F
Benvenuti
D000818:Animals; D002450:Cell Communication; D016764:Cell Polarity; D003713:Dendritic Cells / Q000502:physiology*; D004927:Escherichia coli Infections / Q000276:immunology; D005260:Female; D054992:Immunological Synapses / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D022101:Microtubule-Organizing Center / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
D018664:Interleukin-12; D007371:Interferon-gamma; D020764:cdc42 GTP-Binding Protein