Cytokine-dependent modification of IL-12p70 and IL-23 balance in dendritic cells by ligand activation of Valpha24 invariant NKT cells.
CD1d-restricted invariant NKT (iNKT) cells play crucial roles in various types of immune responses, including autoimmune diseases, infectious diseases and tumor surveillance. The mechanisms underlying their adjuvant functions are well understood. Nevertheless, although IL-4 and IL-10 production characterize iNKT cells able to prevent or ameliorate some autoimmune diseases and inflammatory conditions, the precise mechanisms by which iNKT cells exert immune regulatory function remain elusive. This study demonstrates that the activation of human iNKT cells by their specific ligand alpha-galactosylceramide enhances IL-12p70 while inhibiting the IL-23 production by monocyte-derived dendritic cells, and in turn down-regulating the IL-17 production by memory CD4(+) Th cells. The ability of the iNKT cells to regulate the differential production of IL-12p70/IL-23 is mainly mediated by a remarkable hallmark of their function to produce both Th1 and Th2 cytokines. In particular, the down-regulation of IL-23 is markedly associated with a production of IL-4 and IL-10 from iNKT cells. Moreover, Th2 cytokines, such as IL-4 and IL-13 play a crucial role in defining the biased production of IL-12p70/IL-23 by enhancement of IL-12p70 in synergy with IFN-gamma, whereas inhibition of the IFN-gamma-promoted IL-23 production. Collectively, the results suggest that iNKT cells modify the IL-12p70/IL-23 balance to enhance the IL-12p70-induced cell-mediated immunity and suppress the IL-23-dependent inflammatory pathologies. These results may account for the long-appreciated contrasting beneficial and adverse consequence of ligand activation of iNKT cells.
Uemura
Yasushi
Y
Department of Stem Cell Biology and Regenerative Medicine, Kansai Medical University, Osaka, Japan. uemuraya@takii.kmu.ac.jp
Liu
Tian-Yi
TY
Narita
Yayoi
Y
Suzuki
Motoharu
M
Nakatsuka
Ryusuke
R
Araki
Tomoyuki
T
Matsumoto
Masahito
M
Iwai
Leo Kei
LK
Hirosawa
Narumi
N
Matsuoka
Yoshikazu
Y
Murakami
Mari
M
Kimura
Takashi
T
Hase
Makoto
M
Kohno
Hirao
H
Sasaki
Yutaka
Y
Ichihara
Yasuko
Y
Ishihara
Osamu
O
Kikuchi
Hirosato
H
Sakamoto
Yasushi
Y
Jiao
Shun-Chang
SC
Senju
Satoru
S
Sonoda
Yoshiaki
Y
D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005699:Galactosylceramides / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D021122:Protein Subunits / Q000096:biosynthesis / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*
D016207:Cytokines; D005699:Galactosylceramides; D053759:Interleukin-23; D008024:Ligands; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C528689:Valpha24 protein, human; C493154:alpha-galactosylceramide; D018664:Interleukin-12