Indiana University-Purdue University Indianapolis (IUPUI) / The differentiation of naïve CD4+ T cells into subsets of T helper cells (Th) is an
essential process that impacts host defense and the pathogenesis of immunemediated
diseases. Signal transducers and activators of transcription (STAT)
proteins, activated downstream of instructive cytokines, dictate and perpetuate
the lineage decision of Th cells through both positive and negative effects. This
is accomplished by regulating transcription factors, surface receptors and
promoting epigenetic changes in gene expression through chromatin remodeling.
Transforming growth factor-β1 (TGF-β1) can induce Foxp3 in developing Th cells
and these Foxp3-expressing adaptive T regulatory cells (aTregs) are able to
suppress inflammation in vitro and in vivo. To define the mechanism by which
STAT proteins regulate Th cell pro- and anti-inflammatory phenotypes, we
examined T cells deficient in Stat3, Stat4, and Stat6 as well as T cells expressing
two STAT4 isoforms after being cultured in the presence or absence of TGF-β1
and cytokines known to be instructive in Th cell development. The negative
effects of STAT proteins are demonstrated by our results indicating STAT3,
STAT4 and STAT6 proteins activated downstream of the instructive cytokines IL-
6, IL-12 and IL-4, respectively, negatively regulate the development of TGF-β
induced Foxp3 and aTreg development. STAT3, STAT4, and STAT6 utilize a
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Mark H. Kaplan, Ph.D., Chair
common mechanism to inhibit aTreg generation by inhibiting STAT5, a positive
regulator of Foxp3 expression, from binding to the Foxp3 gene. STAT proteins
positively effecting inflammatory immunity are demonstrated by our analysis of
STAT4 isoforms and their ability to regulate the production of proinflammatory
cytokines downstream of IL-12. STAT4β, a STAT4 splice isoform that lacks a Cterminal
domain, and STAT4α, a full-length isoform are both capable of
mediating inflammatory cell development. However, STAT4β promotes greater
inflammation in vivo than STAT4α independent of its ability to repress Foxp3.
Instead, the inflammation correlates with STAT4 isoform-dependent expression
of inflammatory cytokines. Thus, cytokine-stimulated STAT proteins orchestrate
T helper cell pro- and anti-inflammatory cell phenotypes.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/1872 |
| Date | 19 March 2009 |
| Creators | O'Malley, John Thomas |
| Contributors | Kaplan, Mark H., Blum, Janice S., Clapp, D. Wade, Travers, Jeffrey B. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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