Laddha, S. | Search bioRxiv

bioRxiv2025

Single-Cell Atlas of CD4+ T-Helper 2 Cells Reveals Distinct Cytokine Functions Across Diseases

Despite the prevalence of autoimmune diseases, treatment options for specific conditions remain limited. These diseases are driven by three types of inflammatory pathways, each orchestrated by different T-helper cell subsets; however, a comprehensive atlas capturing their diverse functions across conditions and tissues is lacking. One of these subsets, CD4+ T-helper type 2 (Th2) cells, is a relatively infrequent immune cell population that plays a central role in orchestrating type 2 inflammation. In this study, we developed the first comprehensive CD4+Th2 single-cell atlas by analyzing the BioTuring database, which has data from over 300 million cells. This atlas integrates data from 52 studies, comprising a total of 39,243 cells derived from 9 major tissues, representing over 30 distinct diseases. Leveraging this atlas, we confirmed a rarely recognized CD4+Th2 cell population co-expressing IL22 and IL13 observed exclusively in atopic dermatitis and not in other allergic conditions. By integrating single-cell data with other "omics" technologies, our analysis suggests distinct downstream effects of IL22 and IL13, highlighting the potential for combination therapy to enhance treatment outcomes for AD patients. Additionally, by utilizing data derived from the wide range of diseases, tissues, and time points included in this atlas, we re-confirmed the unique connection between IL9 expression and conditions related to allergen exposure. Pseudotime analysis detailed CD4+Th2 cytokine dynamics upon allergen stimulation, showing a shift from early IL2 and IL4 expression to later IL9 and IL5, with IL13 consistently expressed, and further revealed that IL9 production was transient. Collectively, these findings reveal distinct, context-dependent CD4+Th2 cytokine functions, opening the potential for identifying novel therapeutic strategies for allergic and inflammatory diseases.

immunology↗

bioRxiv2017

ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup

The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

cancer biology↗