IRF-4-Binding Protein Inhibits Interleukin-17 and Interleukin-21 Production by Controlling the Activity of IRF-4 Transcription Factor

Abstract

The TH17 lineage is a novel CD4+ T cell effector subset that plays a key role in inflammatory and autoimmune responses, via its ability to produce IL-17 and IL-21. Given the potentially deleterious effects of TH17 cells, their generation needs to be strictly controlled. The regulatory pathways that prevent the inappropriate development of TH17 cells have not been fully elucidated. IRF-4 is a transcription factor that has recently emerged as a key regulator of TH17 differentiation. Our laboratory has isolated a protein, which interacts with IRF-4, that we have termed IBP (IRF-4 Binding Protein). Our studies previously demonstrated that IBP can act as an activator of Rho GTPases and that mice deficient in IBP develop a lupus-like syndrome upon aging. Here we show that TCR transgenic IBP deficient mice rapidly develop rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology observed in the absence of IBP is associated with an enhanced responsiveness of T cells to low-levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. Furthermore, we demonstrate that the effect of IBP on cytokine production is due to its ability to sequester IRF-4 and prevent it from targeting the transcriptional regulatory regions of the IL-17 and IL-21 genes. Consistent with this finding, the enhanced ability of IBP deficient T cells to produce IL-17 and IL-21 is abolished by the concurrent lack of IRF-4. Taken together these studies suggest that IBP plays a key regulatory role in the prevention of T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 + T cells

“…These data parallel observations in late stages of B-cell development (12) and in generation of Th-cell subsets (13)(14)(15)(16)(17)(18) and thus support the idea of conserved transcriptional modules regulating peripheral differentiation of adaptive lymphocytes (33). Values for nonspecific binding (as determined by using control IgG) were subtracted; nd, not detectable.…”

“…In CD4 + T cells, IRF4 is crucial for the differentiation into T helper (Th) subsets such as Th2, Th9, Th17, and Tfh cells (13)(14)(15)(16)(17)(18). Mechanistically, IRF4 controls B-cell and dendritic cell differentiation by cooperative DNA binding with TFs of the Ets family on Ets-IRF composite elements (EICE) as well as by cooperation with basic leucine zipper transcription factor ATF-like (BATF)-JUN heterodimers in binding to AP-1-IRF4 composite elements (AICE) (19)(20)(21)(22)(23).…”

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

“…These results suggest that IRF-4 suppresses BCR/ABL transformation by interacting with other proteins. Another IRF-4 binding protein is IBP (31). In addition to inhibiting IRF-4's DNA binding, IBP has been shown to function as an activator for Rac (38,39).…”

“…The transcription regulatory function of IRF-4 can be modulated by IRF-4-binding protein (IBP) and FKBP52, which were shown to interact with IRF-4 and inhibit IRF-4's DNA binding (31,32). It is possible that the DNA binding mutants of IRF-4 may sequestrate negative regulators, allowing the endogenous wild-type IRF-4 to suppress BCR/ABL transformation by regulating gene expression.…”

Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells

“…It is now known that transcription factors RORgt and STAT3 are critical and required for the development of Th17 cells (6,7). Recent studies further demonstrated that IFN regulatory factor-4 is also necessary for Th17 cell differentiation (8). TGF-b and IL-6, or TGF-b and IL-21, are critical cytokines for the initiation of mouse Th17 cell differentiation (9)(10)(11)(12)(13).…”