Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Abstract

Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasmacytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, antierythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b + cells that produced IL-6. We also generated IL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasmacytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production. Eur. J. Immunol. 2012Immunol. . 42: 1999Immunol. -2009 Introduction CD4 + T helper (Th) cells are a subcategory of T lymphocytes that play a central role in modulating immune responses. Classically, naïve CD4 + T cells have been thought to differentiate into two cell types, Th1 and Th2 cells. This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al. [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of 3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4]. Expression of the transcription factor retinoic acid related orphan receptor gamma-t (RORγt) is required for the differentiation of Th17 cells [5,6]. The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11]. Since its discovery i...

Overexpression of GATA-3 in T Cells Accelerates Dextran Sulfate Sodium-Induced Colitis

“…Transgenic mice overexpressing T-bet, GATA-3, or RORγt under the control of the CD2 promoter were generated in our laboratory, as previously described [12, 28, 29]. Mice were fed a normal diet comprised of commercial laboratory chow (MF, Oriental Yeast Co., Ltd., Tokyo, Japan) and were maintained under specific pathogen-free conditions in the Laboratory Animal Resource Center of the University of Tsukuba.…”

“…T-bet, GATA-3, and retinoic acid-related orphan receptor gamma-t (RORγt) are known as Th1 [25], Th2 [30, 31], and Th17 lineage commitment transcription factors [14, 27], respectively. We previously generated Th1 dominant (T-bet transgenic (Tg)) mice [12], Th2 dominant (GATA-3 Tg) mice [29], and Th17 dominant (RORγt Tg) mice [28]. In this study, we used the Th1, Th2, and Th17 dominant mice to elucidate the roles of T helper cells in DSS colitis.…”

Transcription Factors GATA-3 and RORγt Are Important for Determining the Phenotype of Allergic Airway Inflammation in a Murine Model of Asthma

“…Transgenic mice overexpressing GATA-3 or RORgt under the control of the CD2 promoter were generated in our laboratory, as previously described (10,11). All animal studies were approved by the Institutional Review Board.…”

Th17-biased RORγt transgenic mice become susceptible to a viral model for multiple sclerosis

“…To generate RORγt Tg mice, a full-length cDNA encoding the murine RORγt protein was inserted into a VA CD2 transgene cassette that contained the upstream gene regulatory region and locus control region of the human CD2 gene (37). The RORγt Tg mice were maintained as heterozygotes for the transgene by breeding them with wild-type C57BL/6 mice.…”

“…To determine whether a preexisting bias (gain-of-function mutation) toward Th17 immune responses would influence the susceptibility to a demyelinating disease, we have established transgenic (Tg) mice on the resistant C57BL/6 mouse background that overexpress RORγt in T cells and are biased toward a Th17 immune response (37). Since C57BL/6 mice have poor Th17 induction (33), these mice will allow us to investigate the role of Th17 cells in TMEV infection without the use of adjuvants.…”