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Highlights: [•] TCR-negative IEL lines are derived from refractory celiac disease II patients. [•] Dendritic cells (DCs) induce proliferation and inhibit apoptosis of such RCDII lines. [•] DC-induced proliferation of RCDII lines is independent of IL-15 or HLA genotype. [•] IFNγ and CXCL10 is produced by cocultures of DC and RCDII lines. [•] DC may therefore contribute to uncontrolled expansion of RCDII cells in vivo. [ABSTRACT FROM AUTHOR]

Objective Refractory coeliac disease type II (RCDII) is a severe complication of coeliac disease (CD) characterised by aberrant intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3-CD7+icCD3+ phenotype. In approximately 40% of patients with RCDII these lymphocytes develop into an invasive lymphoma. In the current study we aimed to identify the physiological counterpart of these cells. Design RCDII cell lines were compared with T-cell receptor positive (TCR+) IEL (T-IEL) lines by microarray analysis, real-time quantitative PCR and flow cytometry. This information was used to identify cells with an RCDIIassociated phenotype in duodenal biopsies from nonrefractory individuals by multicolour flow cytometry. Results RCDII lines were transcriptionally distinct from T-IEL lines and expressed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3-CD7+icCD3+ phenotype, the RCDII lines were distinguishable from other lymphocyte subsets by the absence of CD56, CD127 and CD34. Cells matching this surface lineage-negative (Lin-) CD7+CD127-CD34- phenotype expressed a functional interleukin-15 (IL-15) receptor and constituted a significant proportion of IELs in duodenal specimens of patients without CD, particularly children, and were also found in the thymus. In patients without CD, the Lin-CD7+CD127-CD34- subset was one of four subsets within the CD3-CD7+icCD3+ population that could be distinguished on the basis of differential expression of CD56 and/or CD127. Conclusion Our studies indicate that the CD3-CD7+icCD3+ population is heterogeneous and reveal the existence of a Lin- subset that is distinct from T, B, NK and lymphoid tissue inducer cells. We speculate that this IL-15 responsive population represents the physiological counterpart of aberrant cells expanded in RCDII and transformed in RCDII-associated lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: The receptor tyrosine kinase c-Kit is important for mast cell differentiation, proliferation, and cytokine release. Recently, we reported that c-Kit acts as an intermediate signalling molecule regulating IL-33-induced signalling and effector functions in mast cells. Here, we investigated the influence of c-Kit on the IL-1β-induced signalling and effector functions in HMC mast cell lines. HMC-cells were stimulated with IL-1β and the resulting signalling and cytokine responses were analysed. Furthermore, we used pharmacological inhibitors to investigate the relevance of several signalling molecules for the IL-1β-induced signalling and cytokine responses. Treatment of HMC-cells with the c-Kit inhibitor STI571 blocked the IL-1β-induced activation of Erk1/2 and JNK1/2 but not p38 and NFκB. Furthermore, inhibition of these signalling pathways blocked the IL-6 production in HMC-cells. These findings indicate that IL-1β-induced signalling in mast cells branches into c-Kit- dependent and -independent pathways, both relevant for IL-6 release. Therefore, c-Kit is an important regulator of IL-1 receptor 1-induced signalling and effector functions in HMC-cells. [Copyright &y& Elsevier]

Summary Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues. Highlights • In contrast to mice, human ILCs are less strictly compartmentalized • ILC subset composition is differentially impacted by tissue localization • Tissue environment drives transcriptional heterogeneity in a subset-dependent way • ILC1 exhibit greater transcriptional heterogeneity in mucosal versus lymphoid sites Innate lymphoid cells (ILC) critically regulate tissue immunity and homeostasis in mice, but limited access to healthy human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Yudanin and colleagues provide a comprehensive map of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues. [ABSTRACT FROM AUTHOR]

Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin-IELs) in the duodenum. In ~50% of patients with RCDII, these Lin-IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of thesemalignant Lin-IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin-IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL. Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin-IELs and CD3-CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is a common CD4 + T cell mediated enteropathy driven by gluten in wheat, rye, and barley. Whilst clinical feeding studies generally support the safety of oats ingestion in CD, the avenin protein from oats can stimulate intestinal gluten-reactive T cells isolated from some CD patients in vitro . Our objective was to establish whether ingestion of oats or other grains toxic in CD stimulate an avenin-specific T cell response in vivo . We fed participants a meal of oats (100 g/day over 3 days) to measure the in vivo polyclonal avenin-specific T cell responses to peptides contained within comprehensive avenin peptide libraries in 73 HLA-DQ2.5 + CD patients. Grain cross-reactivity was investigated using oral challenge with wheat, barley, and rye. Avenin-specific responses were observed in 6/73 HLA-DQ2.5 + CD patients (8%), against four closely related peptides. Oral barley challenge efficiently induced cross-reactive avenin/hordein-specific T cells in most CD patients, whereas wheat or rye challenge did not. In vitro , immunogenic avenin peptides were susceptible to digestive endopeptidases and showed weak HLA-DQ2.5 binding stability. Our findings indicate that CD patients possess T cells capable of responding to immuno-dominant hordein epitopes and homologous avenin peptides ex vivo , but the frequency and consistency of these T cells in blood is substantially higher after oral challenge with barley compared to oats. The low rates of T cell activation after a substantial oats challenge (100 g/d) suggests that doses of oats commonly consumed are insufficient to cause clinical relapse, and supports the safety of oats demonstrated in long-term feeding studies. [ABSTRACT FROM AUTHOR]

A summary is presented of an article published online at http://dx.doi.org/10.1126/science.aar6221 concerning research into a orally active small molecule that mimics binding and functionality of the broadly neutralizing antibody CR6261 in influenza A HA. It states the small molecule acts as a fusion inhibitor and inhibits conformational changes and neutralizes a number of emerging, seasonal, and pandemic group 1 influenza A viruses.