The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis.
IL-12 is essential for invariant NKT (iNKT) cells because it can maintain a functionally active population and promote a cytokine profile that is assumed to be mainly of the pro-Th1 type. We used the murine concanavalin A (Con A)-induced hepatitis model, in which iNKT cells, IL-12, IL-4, and IFN-gamma are equally requisite, to reevaluate this issue. We demonstrate that IL-12 interacts directly with iNKT cells, contributes to their recruitment to the liver, and enhances their IL-4 production, which is essential for disease onset. IL-12-deficient mice were less susceptible to experimental hepatitis and their iNKT cells produced less IL-4 than their wild-type counterpart. A normal response could be restored by IL-12 injection, revealing its importance as endogenous mediator. In accordance with this observation, we found that iNKT cells expressed the IL-12R constitutively, in contrast to conventional T cells. Furthermore, the physiological relevance of our data is supported by the lower susceptibility to disease induction of NOD mice, known for their inherent functional and numerical abnormalities of iNKT cells associated with decreased iNKT cell-derived IL-4 production and low IL-12 secretion. Taken together, our findings provide the first evidence that IL-12 can enhance the immune response through increased IL-4 production by iNKT cells, underscoring once more the functional plasticity of this subset.
Zhu
Ren
R
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris V, Hôpital Necker, 161 Rue de Sèvres, 75783 Paris Cedex 15, France.
Diem
Séverine
S
Araujo
Luiza M
LM
Aumeunier
Aude
A
Denizeau
Jordan
J
Philadelphe
Emilie
E
Damotte
Diane
D
Samson
Michel
M
Gourdy
Pierre
P
Dy
Michel
M
Schneider
Elke
E
Herbelin
André
A
D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D006520:Hepatitis, Animal / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D016207:Cytokines; D053711:Interleukin-12 Receptor beta 1 Subunit; D003208:Concanavalin A; D018664:Interleukin-12; D015847:Interleukin-4