IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival.

Innate lymphoid cells (ILCs) including lymphoid tissue-inducer (LTi) cells, IL-22-producing NKp46 + innate cells and IL-13-producing nuocytes play important roles in regulating intestinal microbiota, defence against pathogens and formation of lymphoid tissue [1][2][3][4] . Their development is dependent on Id2 and Rorγt or Rorα 5-7 . Lineage tracing experiments have shown that the common lymphoid precursor gives rise to nuocytes, LTi cells and NKp46 + ILCs 6,8,9 , but these studies have not deciphered the discrete steps and transcription factors that specify ILC subset development, activation and maintenance. Whether NKp46 + ILCs arise directly from LTi cells, or rather represent a separate lineage that diverges earlier in development, remains controversial [10][11][12] . We investigated the requirement for the transcriptional master regulator T-bet (encoded by Tbx21) which is critical for the development of both T cells and NK cells 13,14 , in driving differentiation of ILC populations. Here we report that T-bet played an essential role for the development of NKp46 + ILCs, but was dispensable for LTi cells or nuocytes. Tbx21 +/+ LTi cells adopted an NKp46 + phenotype in vitro and in vivo but not in the absence of Tbx21. Decrease of T-bet expression coordinately reduced Notch1 and Notch2 and we show Notch signaling is necessary for the transition of LTi cells into NKp46 + ILCs. In addition, Tbx21 −/− mice have an accumulation in CD4 − LTi cells and differentiation into NKp46 + ILCs came solely from this population. Our results pinpoint T-bet as the critical regulator of NKp46 + ILC differentiation by regulation of Notch2 signaling. NKp46 + cells are an important element of the protective intestinal mucosal cellular arsenal, and here, we uncover the distinct molecular pathways that guide the development of NKp46 + ILCs. Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author InformationThe authors declare no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2014 July 01. Supplementary Fig. 2).Analysis of T-bet expression in innate lymphocyte populations by intracellular staining and mRNA levels revealed high expression of T-bet in both NKp46 + ILCs and NK (lin − Rorγt − NKp46 + NK1.1 + ) cells isolated from the intestine, while T-bet was not expressed in LTi cells (Fig. 1c). The related T-box factor Eomes, that performs similar functions to Tbet in CD8 + T cells and NK cells, was not expressed in NKp46 + ILCs or LTi cells ( Supplementary Fig. 3a). Thus, T-bet appears to play a crucial role in the development of NKp46 + ILCs. Similar to T-bet, Blimp1 (encoded by Prdm1) was strongly differentially expressed between LTi and NKp46 + ILC populations ( Supplementary Fig. 3b). However, mice homozygously deficient for Blimp1 (Blimp1 gfp/gfp ) did not show any apparent defect in the development of ILC subsets ( Supplementary Fig. 3c). Thus, Blimp1 is dispensable for ILC differentiation while T-b...

Retinoic acid attenuates colitis and is associated with increased IL-22 production from γδ T cells and innate lymphoid cells and enhanced antimicrobial peptide expression.

The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory

Intestinal T cells and group 3 innate lymphoid cells (ILC3) control the composition of the microbiota and gut immune responses. Within the gut there coexists ILC3 subsets which either express or lack the Natural cytoxicity receptor (NCR) NKp46. We identify here the transcriptional signature associated with the T-bet-dependent differentiation of NCR− ILC3 into NCR+ ILC3. Contrary to the prevailing view, we show by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR+ ILC3 were redundant for the control of mouse colonic infections with Citrobacter rodentium in the presence of T cells. However, NCR+ ILC3 were essential for cecum homeostasis. Our data show that interplay between intestinal ILC3 and adaptive lymphocytes results in robust complementary fail-safe mechanisms ensuring gut homeostasis.

Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.