Abstract
The AP-1 transcription factor JunB plays crucial roles in multiple biological processes, including placental formation and bone homeostasis. We recently reported that JunB is essential for development of Th17 cells, and thus Junb-deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4+ T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4+ T cells (Junbfl/flCd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis because of impaired development of regulatory T (Treg) cells. Production of interleukin (IL)-2 and expression of CD25, a high affinity IL-2 receptor component, were decreased in Junb-deficient CD4+ T cells in vitro and in vivo. Naive CD4+ T cells from Junbfl/flCd4-Cre mice failed to differentiate into Treg cells in the absence of exogenously added IL-2 in vitro. A mixed bone marrow transfer experiment revealed that defective Treg development of Junb-deficient CD4+ T cells was not rescued by co-transferred wild-type cells, indicating a significance of the cell-intrinsic defect. Injection of IL-2-anti-IL-2 antibody complexes induced expansion of Treg cells and alleviated DSS-induced colitis in Junbfl/flCd4-Cre mice. Thus JunB plays a crucial role in the development of Treg cells by facilitating IL-2 signaling.
Highlights
The AP-1 transcription factor JunB, which is encoded by the immediate early gene Junb, mediates multiple biological processes including placentation, suppression of myeloid cell proliferation, and maintenance of bone and skin homeostasis.[1,2,3,4] JunB is a basic leucine zipper protein and forms an AP-1 complex by dimerizing with other bZIP proteins, such as Fos or BATF family members
Mice lacking Junb in CD4+ T cells are resistant to T cell-mediated autoimmune disease models We previously reported that Junbfl/flMeox2Cre mice, in which Junb is deleted in all tissues, are resistant to EAE.[5]
To examine the role for JunB in other T cellmediated disease models, we employed an intestinal inflammation model induced by injection of the anti-CD3 agonistic antibody.[26]
Summary
The AP-1 transcription factor JunB, which is encoded by the immediate early gene Junb, mediates multiple biological processes including placentation, suppression of myeloid cell proliferation, and maintenance of bone and skin homeostasis.[1,2,3,4] JunB is a basic leucine zipper (bZIP) protein and forms an AP-1 complex by dimerizing with other bZIP proteins, such as Fos or BATF family members. Regulatory T (Treg) cells, specified by expression of the transcription factor forkhead box P3 (Foxp3), play crucial roles in maintenance of homeostasis by limiting multiple immune responses.[15,16,17] It has been shown that Treg cells ameliorate DSS-induced colitis.[18,19] Development of Treg cells requires IL-2 signaling, as indicated by the fact that mice deficient in IL-2 or its receptor subunits exhibit a marked reduction in Treg cells, leading to lethal autoimmune disorders.[20] Among the three subunits. Injection of immune complexes composed of IL-2 and anti-IL-2 antibody induced upregulation of CD25 and subsequent expansion of Treg cells, resulting in attenuation of DSS-induced colitis in Junbfl/flCd4-Cre mice. JunB plays a crucial role in the development of Treg cells by upregulating IL-2 signaling, thereby attenuating DSS-induced colitis
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