RIPK3 and caspase-8 interpret cytokine signals to regulate ILC3 survival in the gut.

Group 3 innate lymphoid cells (ILC3s) are abundant in the developing or healthy intestine to critically support tissue homeostasis in response to microbial colonization. However, intestinal ILC3s are reduced during chronic infections, colorectal cancer, or inflammatory bowel disease (IBD), and the mechanisms driving these alterations remain poorly understood. Here we employed RNA sequencing of ILC3s from IBD patients and observed a significant upregulation of RIPK3, the central regulator of necroptosis, during intestinal inflammation.

Causes Persistent Subclinical Infection and Elicits Innate and Adaptive Immune Responses in C57BL/6J, BALB/cJ and J:ARC(S) Mice Following Exposure to Shedding Mice.

(Cm) has reemerged as a moderately prevalent infectious agent in research mouse colonies. Despite its' experimental use, few studies evaluate Cm's effects on immunocompetent mice following its natural route of infection. A Cm field isolate was administered (orogastric gavage) to 8-week-old female BALB/cJ (C) mice.

CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation.

Interleukin (IL-)23 is a major mediator and therapeutic target in chronic inflammatory diseases that also elicits tissue protection in the intestine at homeostasis or following acute infection. However, the mechanisms that shape these beneficial versus pathological outcomes remain poorly understood. To address this gap in knowledge, we performed single-cell RNA sequencing on all IL-23 receptor-expressing cells in the intestine and their acute response to IL-23, revealing a dominance of T cells and group 3 innate lymphoid cells (ILC3s).

Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma.

One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance.

Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation.

Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death.

Antigen-presenting innate lymphoid cells orchestrate neuroinflammation.

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis.

PLCγ1‑dependent invasion and migration of cells expressing NSCLC‑associated EGFR mutants.

The increased tyrosine kinase activity of non‑small cell lung cancer (NSCLC)‑associated epidermal growth factor receptor (EGFR) mutants results in deregulated pathways that contribute to malignant cell survival, tumor progression and metastasis. Previous studies investigating lung cancer‑associated EGFR have focused on the prognostic implications of receptor kinase mutations in patients with NSCLC; however, the role of EGFR mutations in tumor cell invasion and migration remains undetermined. The present study was designed to investigate the role of NSCLC‑associated mutant EGFR‑driven signaling pathways in cell proliferation and invasion.

A Synthetic CD8α:MyD88 Coreceptor Enhances CD8 T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens.

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8 T-cell responses to weakly immunogenic and poorly expressed tumor antigens.

Cross-talk between 4-1BB and TLR1-TLR2 Signaling in CD8+ T Cells Regulates TLR2's Costimulatory Effects.

The activation of TLR-MyD88 (Toll-like receptor-myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2-stimulated and unstimulated T-cell receptor transgenic "pmel" and MyD88(-/-) pmel CD8(+) T cells and identified changes in the expression of several TNF family members.

Proteomic analysis of HEK293 cells expressing non small cell lung carcinoma associated epidermal growth factor receptor variants reveals induction of heat shock response.

In view of the fact that certain non small cell lung carcinoma associated epidermal growth factor receptor mutations keep the receptor constitutively active, the downstream effectors of altered activity of mutant receptors are largely unknown. By 2D gel electrophoresis and MALDI-TOF/MS analysis, we showed that increased activity of EGFR mutants, L858R, L861Q and A871G induce heat shock proteins such as Hsp70, Hsp60, Hsp90B1, Hsp5a, Hsp71 and few transcriptional factors. Of which, Hsp70 was observed to be regulated more selectively to L861Q mutant.

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies.

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death.

TLR agonists: our best frenemy in cancer immunotherapy.

Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth.