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Promoter Elements During Th Cell Differentiation1
Division of Rheumatology, Departments of
*
Medicine and
Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Department of Pediatrics and
§
Section of Immunobiology, Yale University School of Medicine, and
¶
Howard Hughes Medical Institute, New Haven, CT 06510
Before they can deliver their effector functions, CD4+
Th cells must differentiate into Th1 or Th2 subsets. We have prepared
reporter transgenic mice that express the luciferase gene under the
control of proximal (prox.IFN-
) and distal
(dist.IFN-) regulatory elements from the IFN-
promoter to permit investigation of mechanisms that regulate IFN-
gene transcription during Th cell differentiation. Precursor Th cells
(pTh) contain high levels of cAMP response element binding
protein-activation transcription factor-1 (CREB-ATF1) proteins
that bind these promoter elements from the IFN- gene, and these
cells fail to express promoter activity. Restimulated effector Th (eTh)
cells have reduced levels of CREB-ATF1 proteins, their nuclear extracts
exhibit reduced CREB-ATF1 binding and greater Jun and Jun-ATF2 binding
to dist.IFN-, and eTh cells express promoter activity.
CREB directly competes with effector T cell nuclear proteins for
dist.IFN- binding, and overexpression of CREB inhibits
both prox.IFN-- and dist.IFN--directed
transcription in Jurkat T cells. IL-12-stimulated Th1 differentiation
increases dist.IFN- activity in restimulated eTh1 cells;
eTh1 nuclear extracts form increased levels of
Jun-ATF2-dist.IFN- complexes. Taken together, these data
suggest that both de-repression and trans-activation
contribute to the induction of IFN- gene transcription during Th1
differentiation.
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