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Are Required for IL-12 But Not Prostaglandin E2 Secretion by Microglia During Antigen Presentation to Th1 Cells1
*
Laboratory of Organ and System Pathophysiology, Istituto Superiore di Sanità, Rome, Italy; and
Roche Milano Ricerche, Milan, Italy
IL-12 and PGE2 promote and inhibit, respectively, the
development of Th1 responses. Production of these mediators by APC
residing in the central nervous system (CNS) may be involved in the
local regulation of the T cell phenotype during infectious and
autoimmune CNS diseases. In the present study we have examined IL-12
and PGE2 secretion by cultured microglia and astrocytes
from the mouse brain upon Ag-dependent interaction with
I-Ad-restricted, OVA323–339 specific TCR
transgenic Th1 and Th2 cell lines. We show that microglia, which
restimulate efficiently both Th1 and Th2 cells, secrete IL-12 upon
Ag-dependent interaction with Th1, but not with Th2 cells. Th1-driven
IL-12 production depends on TCR ligation by MHC class II/peptide
complexes, CD40 engagement on microglia, and IFN-
secretion by
activated Th1 cells. Th1 and, to a lesser extent, Th2 cells also
stimulate the production of PGE2 by microglia. T
cell-mediated induction of PGE2 requires MHC class
II/peptide/TCR interactions but does not depend on CD40 engagement or
on the presence of IFN-. Astrocytes, which preferentially activate
Th2 cells, fail to produce IL-12 and secrete negligible amounts of
PGE2 upon interaction with either Th1 or Th2 cells. These
results suggest that during CNS infection or immunopathology, IL-12
produced by microglia upon Ag-specific interaction with Th1 cells may
further skew the immune response to Th1, whereas the T cell-dependent
production of PGE2 by microglia may represent a negative
feedback mechanism, limiting the propagation of Th1
responses.
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