Signaling via the kinase p38α programs dendritic cells to drive TH17 differentiation and autoimmune inflammation.
Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices remains unclear. We report here that the mitogen-activated protein kinase p38α programmed DCs to drive the differentiation of the T(H)17 subset of helper T cells. Deletion of p38α in DCs protected mice from T(H)17 cell-mediated autoimmune neuroinflammation, but deletion of p38α in macrophages or T cells did not. We also found that p38α orchestrated the expression of cytokines and costimulatory molecules in DCs and further 'imprinted' signaling via the receptor for interleukin 23 (IL-23R) in responding T cells to promote T(H)17 differentiation. Moreover, p38α was required for tissue-infiltrating DCs to sustain T(H)17 responses. This activity of p38α was conserved in mouse and human DCs and was dynamically regulated by pattern recognition and fungal infection. Our results identify p38α signaling as a central pathway for the integration of instructive signals in DCs for T(H)17 differentiation and inflammation.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Gonghua
G
Huang
Yanyan
Y
Wang
Peter
P
Vogel
Thirumala-Devi
TD
Kanneganti
Kinya
K
Otsu
Hongbo
H
Chi
D000818:Animals; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology*; D017353:Gene Deletion; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009181:Mycoses / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D058504:Th17 Cells / Q000201:enzymology / Q000276:immunology*
D016207:Cytokines; D018123:Receptors, Interleukin; D051192:Receptors, Pattern Recognition; C528688:interleukin-23 receptor, mouse; D048308:Mitogen-Activated Protein Kinase 14