Innate lymphoid type 2 cells maintain eosinophils and alternatively activated macrophages in visceral fat via the production of IL-5 and IL-13.

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago,1 and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins, mediate eosinophil development and survival,2 and tissue recruitment,3 respectively, the processes underlying the basal regulation of these signals remain unknown. Here, we show that serum IL-5 is maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive,4 ILC2 co-express IL-5 and IL-13, which is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP) also stimulates ILC2 through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.

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ing non-thymic self-antigen undergo apoptosis. Apoptosis

Contributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive IL-4 reporter alleles, we demonstrate that basophil IL-4 production occurs by a CD4+ T cell-dependent process restricted to affected peripheral tissues. We genetically marked and specifically deleted basophils and demonstrate that basophils do not mediate TH2 priming in vivo. Two-photon imaging confirmed that basophils do not interact with antigen-specific T cells in lymph nodes, but can engage in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4 and IL-13 in either CD4+ T cells or basophils minimally impacted worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity.

T-cell receptor (TCR)-mediated apoptosis in immature thymocytes and T-cell hybridomas is calcium dependent and can be inhibited by cyclosporin A (CsA). Induction of the orphan steroid receptor Nur77 (NGFI-B) is required for activation-induced apoptosis. Here, we examined the regulation of Nur77 expression, in response to apoptotic TCR signals, which consists of kinase C and calcium pathways. We show that the major control of Nur77 induction is mediated by the calcium signaling pathway. In contrast, protein kinase C signals induce only a low level of Nur77 activity. Nur77 promoter activity parallels its protein levels. CsA decreases both Nur77 protein levels and promoter activity, and the kinetics of CsA inhibition of apoptosis correlates with a decrease in Nur77 protein levels. TCR signals and kinase C signals result in a similar level of Nur77 protein phosphorylation but mediate differential transactivation activity of Nur77. In addition, Nur77 promoter deletion analysis revealed two RSRF (related to serum-responsive factor) binding sites, which can confer calcium and CsA sensitivity on a heterologous promoter. Taken together, our data suggest that the levels of transcriptional induction of Nur77 play an important role during activation-induced apoptosis and that calcium signals regulate a novel CsA-sensitive nuclear factor required for Nur77 transcription in T cells.

The cell cycle in mammalian cells is regulated by a series of cyclins and cyclin-dependent kinases (CDKs). The G 1 /S checkpoint is mainly dictated by the kinase activities of the cyclin D-CDK4 and/or cyclin D-CDK6 complex and the cyclin E-CDK2 complex. These G 1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G 1 phase. In T-cell hybridomas, addition of anti-T-cell receptor antibody results not only in G 1 arrest but also in apoptosis. In searching for a protein(s) which might interact with Nur77, an orphan steroid receptor required for activation-induced apoptosis of T-cell hybridomas, we have cloned a novel human and mouse CDK inhibitor, p19. The deduced p19 amino acid sequence consists of four ankyrin repeats with 48% identity to p16. The human p19 gene is located on chromosome 19p13, distinct from the positions of p18, p16, and p15. Its mRNA is expressed in all cell types examined. The p19 fusion protein can associate in vitro with CDK4 but not with CDK2, CDC2, or cyclin A, B, E, or D1 to D3. Addition of p19 protein can lead to inhibition of the in vitro kinase activity of cyclin D-CDK4 but not that of cyclin E-CDK2. In T-cell hybridoma DO11.10, p19 was found in association with CDK4 and CDK6 in vivo, although its association with Nur77 is not clear at this point. Thus, p19 is a novel CDK inhibitor which may play a role in the cell cycle regulation of T cells.Apoptosis in immature T cells and T-cell hybridomas, which may relate to negative selection during T-cell development, can be initiated by signals through the T-cell receptor-CD3 complex (18,32,33). This process of activation-induced apoptosis (anti-CD3 apoptosis) consists of two distinct phases. The first phase is the cell cycle block at the G 1 /S transition; it is followed by the second phase, with the generation of apoptotic DNA ladders (18). The second phase requires extracellular calcium and can be inhibited by the immunosuppressive drug cyclosporin A (18). We and others have shown that Nur77 (NGFI-B) orphan steroid receptor is induced during anti-CD3 apoptosis through the calcium signals and it plays an essential role in the cell death process (17, 35). Dominant negative Nur77 can block apoptosis but not the interleukin 2 production of anti-CD3-treated T-cell hybridomas (35). Thus, Nur77 is involved in the second phase of anti-CD3 T-cell apoptosis.As alluded to above, anti-CD3 death in T-cell hybridomas is also accompanied by a G 1 cell cycle block. In all organisms studied so far, cell cycle progression is mediated by cyclindependent kinases (CDKs) that consist of a catalytic subunit CDK and a regulatory subunit cyclin. In mammalian cells, cyclin E-CDK2 together with cyclin D-CDK4 and/or cyclin D-CDK6, which are active in the G 1 phase, control the G 1 -to-S transition (23, 24, 28, 31 and references therein). There are at least three different D-type cyclins, with T cells expressing cyclins D2 and D3 and two cyclin D-associating kinases, CDK4 and CDK6. One of their substrates is the retinobl...

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