BackgroundGroup 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation.ObjectiveWe set out to investigate how PGE2 regulates human ILC2 function.MethodsThe effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE2 receptor expression.ResultsPGE2 inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE2 downregulated the expression of IL-2 receptor α (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s.ConclusionOur findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.

SummaryWe measured body composition and resting metabolic rates (RMR) of three dog breeds (Papillons, mean body mass 3.0 kg ( n = 35), Labrador retrievers, mean body mass 29.8 kg ( n = 35) and Great Danes, mean body mass 62.8 kg ( n = 35)) that varied between 0.6 and 14.3 years of age. In Papillons, lean body mass (LBM) increased with age but fat mass (FBM) was constant; in Labradors, both LBM and FBM were constant with age, and in Great Danes, FBM increased with age but LBM was constant. FBM averaged 14.8% and 15.7% of body mass in Papillons and Labradors, respectively. Great Danes were leaner and averaged only 10.5% FBM. Pooling the data for all individuals, the RMR was significantly and positively associated with LBM and FBM and negatively associated with age. Once these factors had been taken into account there was still a significant breed effect on RMR, which was significantly lower in Labradors than in the other two breeds. Using the predictive multiple regression equation for RMR and the temporal trends in body composition, we modelled the expenditure of energy (at rest) over the first 8 years of life, and over the entire lifespan for each breed. Over the first 8 years of life the average expenditure of energy per kg LBM were 0.985, 0.675 and 0.662 GJ for Papillons, Labradors and Great Danes, respectively. This energy expenditure was almost 60% greater for the smallest compared with the largest breed. On average, however, the life expectancy for the smallest breed was a further 6 years (i.e. 14 years in total), whereas for the largest breed it was only another 6 months (i.e. 8.5 years in total).Total lifetime expenditure of energy at rest per kg LBM averaged 1.584, 0.918 and 0.691 GJ for Papillons, Labradors and Great Danes, respectively. In Labradors, total daily energy expenditure, measured by the doubly labelled water method in eight animals, was only 16% greater than the observed RMR. High energy expenditure in dogs appears positively linked to increased life expectancy, contrary to the finding across mammal species and within exotherms, yet resembling observations in other intraspecific studies. These contrasting correlations suggest that metabolism is affecting life expectancy in different ways at these different levels of enquiry.

Background: Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and maintenance of type 2 immune responses. The prostaglandin (PG) D 2 -chemoattractant receptor-homologous molecule expressed on T H 2 cells (CRTH2) receptor axis potently induces cytokine production and ILC2 migration.

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.Keywords: Aiolos r Ikaros r ILC r lenalidomide r NK cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

The NKR Ly49E has several unique characteristics. Unlike most NKRs, Ly49E is highly expressed on fetal NK cells, whereas expression is decreased on bone marrow-derived NK cells in adult mice. To investigate a possible role for Ly49E in NK cell differentiation and function, we have generated an Ly49E KO mouse. Our results show that bone marrow and splenic NK cells are present in normal numbers in Ly49E KO mice, expressing an unaltered panel of NKRs and differentiation markers. Furthermore, cytokine production and cytotoxicity by these cells are unaffected. Surprisingly, WT DX5(-) liver NK cells express high Ly49E levels in fetal and adult mice. Ly49E(+)DX5(-) liver NK cells transferred into Rag-2(-/-)/gc(-/-) mice maintain high Ly49E expression in the liver and differentiate into DX5(+) NK cells in spleen and bone marrow. Ly49E expression is not crucial for liver NK cell differentiation during ontogeny, as the DX5(-)/DX5(+) ratio, the NKR repertoire, and the granzyme B and TRAIL levels are comparable in Ly49E KO versus WT mice, except for lower TRAIL expression on DX5(-) liver NK cells in 20-day-old mice. The TRAIL-, perforin-, and FasL-mediated cytolysis by liver NK cells is unaffected in Ly49E KO mice. Collectively, we show that in addition to high Ly49E expression on fetal NK cells versus low Ly49E expression on conventional NK cells in adult life, Ly49E remains highly expressed on DX5(-) liver NK cells. However, Ly49E expression does not have a crucial role in differentiation and/or function of these NK cells.

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα T lymphocytes, and CD49a liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46CD8ααLy49E cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.

Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/ 6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T1O.