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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2489-2497
IMMUNOBIOLOGY
Calcium signaling inhibits interleukin-12 production and
activates CD83+ dendritic cells that induce Th2
cell development
Mark B. Faries,
Isabelle Bedrosian,
Shuwen Xu,
Gary Koski,
James G. Roros,
Mirielle A. Moise,
Hung Q. Nguyen,
Friederike H. C. Engels,
Peter A. Cohen, and
Brian J. Czerniecki
From the Department of Surgery and the Harrison
Surgical Research Center, University of Pennsylvania, Philadelphia; the
Frederick Cancer Research and Development Center, National Cancer
Institute, MD; and the Center for Surgery Research, Cleveland Clinic
Foundation, OH.
Mature dendritic cells (DCs), in addition to providing
costimulation, can define 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, it 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 serum-free medium
and granulocyte-macrophage colony-stimulating factor to produce
immature DCs, additional overnight culture with either calcium
ionophore (CI) or interferon  (IFN-), tumor necrosis factor-
(TNF-), and soluble CD40L resulted in phenotypically mature DCs that
produced interleukin-8 (IL-8) and displayed marked expression of CD80,
CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-,
TNF-, and soluble CD40L were additionally distinguished by
undetectable CD4 expression, marked secretion of IL-12, IL-6, and
MIP-1 , 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, and preferential ability to promote Th2/Tc2
characteristics. Calcium signaling selectively antagonized IL-12
production by mature DCs activated with IFN-, TNF-, and soluble
CD40L. Although the activation of DCs by calcium signals is largely
mediated through calcineurin phosphatase, the inhibition of IL-12
production by calcium signaling was independent of this enzyme.
Naturally occurring calcium fluxes in immature DCs, therefore,
negatively regulate Dc1 differentiation while promoting Dc2
characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may
have clinical usefulness in treating disease states with excessive
Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
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