STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus

Abstract

Interleukin 1 is a pleiotropic cytokine produced from macrophages and dendritic cells, which induces several responses in T cells including increased proliferation, increased cytotoxic activity, and Th1 differentiation (1). IL-12 activates several signaling pathways that may mediate these biological activities including p38 MAPK and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (2-5). Upon binding of IL-12, both chains of the IL-12 receptor (IL-12R␤1 and IL-12R␤2) heterodimerize and activate the associated JAKs, TYK2, and JAK2. The IL-12R␤2 chain is subsequently tyrosine phosphorylated and recruits STAT4 to a specific docking site where it is itself phosphorylated (6). The phosphorylated STAT4 monomers then homodimerize and translocate into the nucleus. STAT4 is required for many of the functions of IL-12 including the induction of IFN-␥ and the differentiation of Th1 cells (7,8).Once in the nucleus, STAT4 binds to a cognate binding sequence within IL-12 responsive genes to subsequently mediate activation of transcription (9 -11). Several IL-12 responsive genes that require STAT4 for transcriptional activation have been identified including IFN-␥ (7-9, 12), IL-18R␣ (13, 14), ERM (15) and IRF-1 (10, 11). STAT4 may interact with other transcription factors at a promoter through several domains, including the C-terminal "transactivation domain." However, both STAT4 isoforms, STAT4␣ and STAT4␤ (16), the latter of which lacks the C-terminal 40 amino acids encompassing the putative transcription activation domain, are able to activate transcription and mediate many IL-12 responses. This suggests that interactions of other transcription factors with the STAT4 transactivation domain are not required for all STAT4-dependent responses. Furthermore, the events that STAT4 initiates at a promoter, and the kinetics with which they occur have not been characterized.CD25 is the ␣ chain of the high affinity IL-2 receptor complex. CD25 is only expressed upon T cell activation, and expression is further modulated by IL-2 stimulation. Transcription of CD25 is regulated by multiple transcription factors that bind to elements termed positive regulatory regions (PRR) in the CD25 promoter and intronic regions. PRRI is located around 260 nucleotides upstream of the major transcription initiation sites in the mouse gene (Ϫ276 to Ϫ244 in human) (17-19) and binds NF-B and serum response factor (20). PR-RII is around Ϫ100 in the mouse gene (Ϫ137 to Ϫ64 in human) and binds . PRRIII, also known as the IL-2 responsive element (IL-2rE), is located Ϫ1306 to Ϫ1387 in the mouse gene (Ϫ3780 to Ϫ3703 in human), and one of the tandem STAT5 binding sites overlaps a binding site for . In the mouse gene, an additional regulatory element at Ϫ576 to Ϫ667 that contains binding sites for NFAT and AP-1 proteins is also required for T cell receptor-mediated induction of IL-2R␣ chain expression (27). Recently, two additional elements in the human gene have been identified, a CD28 responsive element (CD28rE) at Ϫ8.5 kB t...

Abnormal Immunological Profile and Vaginal Microbiota in Women Prone to Urinary Tract Infections

“…It was shown that the T-cell activation marker CD25 may have been improperly induced in response to IL-12 produced by the APCs. Interestingly, it has been shown that signal transducer and activator of transcription 4 (STAT4) is the critical mediator of IL-12-induced expression of CD25 (35) and that STAT4 deficiency in mice is associated with reduced IFN-␥ levels, accelerated nephritis, and increased mortality (24). Another characteristic of the UTI-prone subjects studied here was the lack of correlation between CD54 T-cell surface expression and TNF-␣ production by DCs.…”

Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses

“…In T cells, STAT4 ChIP has revealed many genes bound and regulated by STAT4, including Ifng , Il12rb2 , and Il2ra (27, 28). Consistent with a broad role for STAT4 in the initiation of type 1 immune responses, IL-12, together with IFN-α and IFN-β, induces IFN-γ production in antiviral T cells via STAT4 (29).…”

Functional Characterization and Gene Expression Analysis of CD4+CD25+ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

“…The implications of enhanced signaling of the IL-12Rb2 pathway on the function or generation of TCDD-CD4 + cells is currently under investigation. Because IL-12-responsive elements can cause chromatin remodeling at the CD25 gene locus and increase CD25 expression (43), IL-12 signaling may be an important pathway for up-regulating CD25 on TCDD-CD4 + cells. The JAK2/STAT4 pathway is also important in the promotion of IFN-γ production; however increased expression of IFN-γ at the transcript or protein level in TCDD-CD4 + cells was not found.…”