Calcium signaling inhibits interleukin-12 production and activates CD83(+)dendritic cells that induce Th2 cell development

Mature dendritic cells (DCs), in addition to providing costimulation, can d efine the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, i t was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in se rum-free medium and granulocyte-macrophage colony-stimulating factor to pro duce immature DCs, additional overnight culture with either calcium ionopho re (CI) or interferon gamma (IFN gamma), tumor necrosis factor-alpha (TNF-a lpha), and soluble CD40L resulted in phenotypically mature DCs that produce d interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and ReIB. DCs matured by IFN-gamma, TNF-alpha, and so luble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1 beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast , DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1 beta, and preferential ability t o promote Th2/Tc2 characteristics. Calcium signaling selectively antagonize d IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and s oluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 productio n by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differen tiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calci um-mobilized DCs may have clinical usefulness in treating disease states wi th excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimm unity. (Blood. 2001;98: 2489-2497) (C) 2001 by The American Society of Hema tology.