Interleukin (IL)-6 is produced by professional antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells. It has been previously shown that APC-derived IL-6 promotes the differentiation of naive CD4+ T cells into effector T helper type 2 (Th2) cells. Here, we have studied the molecular mechanism for IL-6–mediated Th2 differentiation. During the activation of CD4+ T cells, IL-6 induces the production of IL-4, which promotes the differentiation of these cells into effector Th2 cells. Regulation of IL-4 gene expression by IL-6 is mediated by nuclear factor of activated T cells (NFAT), as inhibition of NFAT prevents IL-6–driven IL-4 production and Th2 differentiation. IL-6 upregulates NFAT transcriptional activity by increasing the levels of NFATc2. The ability of IL-6 to promote Th2 differentiation is impaired in CD4+ T cells that lack NFATc2, demonstrating that NFATc2 is required for regulation of IL-4 gene expression by IL-6. Regulation of NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.

We conclude that during imaginal disc development, Dp110 and p60 regulate cell size, cell number and organ size. Our results indicate that Dp110 and p60 signalling can affect growth in multiple ways, which has important implications for the function of signalling through class I(A) PI 3-kinases.

The family of genuine NF-AT transcription factors consists of four members (NF-AT1 [or NF-ATp], NF-AT2 [or NF-ATc], NF-AT3 and NF-AT4 [or NF-ATx]) which are characterized by a highly conserved DNA binding domain (is designated as Rel similarity domain) and a calcineurin binding domain. The binding of the Ca(2+)-dependent phosphatase calcineurin to this region controls the nuclear import and exit of NF-ATs. This review deals (1) with the structure of NF-AT proteins, (2) the DNA binding of NF-AT factors and their interaction with AP-1, (3) NF-AT target genes, (4) signalling pathways leading to NF-AT activation: the role of protein kinases and calcineurin, (5) the nuclear entry and exit of NF-AT factors, (6) transcriptional transactivation by NF-AT factors, (7) the structure and expression of the chromosomal NF-AT2 gene, and (8) NF-AT factors in Th cell differentiation. The experimental data presented and discussed in the review show that NF-AT factors are major players in the control of T cell activation and differentiation and, in all likelihood, also of the cell cycle and apoptosis of T lymphocytes.

SummaryThe expression of the murine interleukin (IL)-2 receptor ␣ chain/CD25 is strongly induced at the transcriptional level after T cell activation. We show here that nuclear factor of activated T cell (NF-AT) factors are involved in the control of CD25 promoter induction in T cells. NFATp and NF-ATc bind to two sites around positions Ϫ 585 and Ϫ 650 located upstream of the proximal CD25 promoter. Immediately 3 Ј from these NF-AT motifs, nonconsensus sites are located for the binding of AP-1-like factors. Mutations of sites that suppress NF-AT binding impair the induction and strong NF-ATp-mediated transactivation of the CD25 promoter in T cells. In T lymphocytes from NF-ATp-deficient mice, the expression of CD25 is severely impaired, leading to a delayed IL-2 receptor expression after T cell receptor (TCR)/CD3 stimulation. Our data indicate an important role for NF-AT in the faithful expression of high affinity IL-2 receptors and a close link between the TCR-mediated induction of IL-2 and IL-2 receptor ␣ chain promoters, both of which are regulated by NF-AT factors. Key words: interleukin 2 receptor • nuclear factor of activated T cells • transcription factors • T cells • NF-AT factorsT he high affinity IL-2 receptor consists of three individual polypeptides, the ␣ , ␤ , and ␥ chains. Although the ␤ and ␥ chains are shared by other lymphokine receptors, the ␣ chain (CD25) is restricted to the IL-2 receptor, and is expressed by a variety of lymphoid cells (for review see reference 1). The induction of CD25 in T cells is controlled at the transcriptional level through two DNA sequence elements, a proximal promoter/enhancer spanning the nucleotides between positions Ϫ 54 and Ϫ 584 in the mouse and Ϫ 64 and Ϫ 276 in humans, and a distal enhancer spanning ‫ف‬ 80 nucleotides around position Ϫ 1350 in the mouse and Ϫ 3750 (or Ϫ 4150, according to another nomenclature) in the human CD25 gene (2-6). The activity of the promoter is rapidly induced by TCR-mediated signals or IL-1, and is controlled by an array of transcription factors, in particular by nuclear factor (NF)-B, Elf-1, SRF, and HMG I(Y). The induction of the distal enhancer is controlled by IL-2, which induces signal transducer and activator of transcription (Stat)5, a member of the family of Stat transcription factors. Stat5 binds in concert with Elf-1, HMG I(Y), and GATA factors to multiple sites of the distal enhancer and contributes to its IL-2-mediated full expression in activated peripheral T lymphocytes (4-6).Nuclear factor of activated T cell (NF-AT) factors comprise a family of transcription factors that contribute to the induced expression of numerous lymphokine and receptor genes in T cells. Similar to NF-B factors, the nuclear translocation and activity of NF-AT factors is stimulated by TCR-mediated signals (for review see reference 7). The DNA-binding domains of NF-AT and NF-B/Rel factors share a common architecture (8) and, therefore, recognize overlapping DNA sequence motifs. These common properties between NF-AT and NF-B (a major regulator o...

The mushroom bodies are bilaterally arranged structures in the protocerebrum of Drosophila and most other insect species. Mutants with altered mushroom body structure have been instrumental not only in establishing their role in distinct behavioral functions but also in identifying the molecular pathways that control mushroom body development. The mushroom body miniature 1 (mbm 1 ) mutation results in grossly reduced mushroom bodies and odor learning deficits in females. With a survey of genomic rescue constructs, we have pinpointed mbm 1 to a single transcription unit and identified a single nucleotide exchange in the 5 untranslated region of the corresponding transcript resulting in a reduced expression of the protein. A daptive behavior of animals and humans requires functional neuronal circuits in the brain. The genetic programs that control the generation of these circuits by providing an adequate number of neurons, establishing neuronal connectivity, and remodeling them during development and in response to external stimuli during adulthood are just beginning to emerge. The mushroom bodies (MBs), a prominent neuropil structure of the insect brain (1), have become an attractive model system to study many aspects of this intricate network. Functional studies have established a role of the MBs in olfactory learning and memory, controlling locomotor activity, performing visual context generalization, and decision making (2, 3). On the other hand, the structural organization and the development of the MBs have been described in great detail in refs. 4-10. In the adult fly Drosophila melanogaster, Ϸ2,500 intrinsic neurons (Kenyon cells) build up one MB. The Kenyon cell bodies are located in the dorsal cortex and extend their dendritic branches into the calyx, where prominent inputs from other brain regions are received. The Kenyon cell axons fasciculate in the peduncle and extend rostroventral, where most of them bifurcate to form a system of medially and dorsally projecting lobes. Each MB arises from a group of four apparently equipotent neuronal stem cells (neuroblasts), each of which generates in a sequential manner several types of Kenyon cells during larval and pupal stages. MB ␥ neurons are born before the mid-third-larval instar, then ␣Ј͞␤Ј neurons are born, and finally the ␣͞␤ neurons are added at pupal stages (6,8). The nomenclature of the Kenyon cells refers to the corresponding dorsally and medially projecting MB lobes in the adult fly (see Fig. 2). More recently, immunohistochemical studies have identified additional subtypes of Kenyon cells (9). Yet, the anatomical description disregards the structural plasticity of the adult MBs as a consequence of changes in living conditions and experience (11). Furthermore, Kenyon cell axons and dendrites undergo massive remodeling during metamorphosis to establish adult-specific branching patterns. The axons of the ␥ neurons, which bifurcate in a dorsal and a medial branch in the larvae, degenerate and regrow only in the medial direction (8,10,(12)(13)(14).What...