Keswani, T. | bioRxiv Science

bioRxiv2025

GPR15 and CD38 define a subset of peripheral blood pathogenic effector Th2 cells associated with active eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergic disease driven by exposure to culprit antigens. Due to the local nature of the inflammation, diagnosis and assessment are limited to invasive procedures. Based on prior single-cell RNA sequencing (scRNA-seq) data linking peripheral GPR15+ pathogenic effector Th2 (peTh2) cells to esophageal tissue peTh2s, we hypothesized the direct involvement of GPR15+ peTh2 cells in EoE pathogenesis and aimed to further evaluate their association with EoE disease status. We subjected samples from subjects with or without EoE to flow cytometry (n = 74 peripheral blood, 17 biopsy) and scRNA-seq (n = 27 peripheral blood, 10 biopsy). Expression of GPR15 by peripheral peTh2 cells was increased in EoE, and these cells expressed increased CD38 in active EoE--findings recapitulated in esophageal biopsies. We also identified a peTh2-associated, CD38-containing gene expression program that peripheral GPR15+ peTh2 cells upregulated in active EoE. The level of upregulation was distinct from other circulating peTh2 cells and was more similar to that seen in esophageal peTh2 cells. An association between expression of GPR15 by peripheral peTh2 cells, the aryl hydrocarbon receptor was strongest in subjects with EoE, suggesting an environmental exposure or susceptibility. The magnitude of GPR15 expression by peripheral peTh2 cells could effectively in discriminate active EoE from no EoE in our study population (AUC 0.93). Our data suggest that EoE-related peTh2 cells are identifiable and accessible in the peripheral blood, and could be exploited in both clinical practice as a non-invasive biomarker and continued investigation into mechanisms driving EoE. One sentence summaryGPR15 marks a subset of peripheral blood pathogenic effector Th2 cells associated with eosinophilic esophagitis (EoE) that upregulate CD38 during active disease - an observation that has potential to be used for non-invasive diagnosis and monitoring of EoE and that has suggests new mechanisms driving this increasingly prevalent allergic disease.

immunology↗

bioRxiv2025

Astrocytes control the Neuroinflammation and ILC2 response through IL-33/ST2 signaling, during protection against Cerebral Malaria in Toxoplasma-P. berghei coinfected Mice

Cerebral malaria (CM) is a complex multi-systemic disorder defined as a diffuse encephalopathy with acute neurological manifestations characterized by alterations in the level of consciousness, deep coma and seizure preceding death. During infection, astrocytes undergo significant morphological and molecular changes, adopting a reactive state that impacts on their functions. This reactivity is characterized by a shift in from a neuroprotective (A2) to a neurotoxic (A1) phenotype, influencing the outcome of the immune response. These phenotypes may vary depending on the chronicity of the infection or multiples infections of the same host. In this study, we investigated how Toxoplasma gondii (Tg) brain infection impacts on the outcome of experimental cerebral malaria (ECM) in mice infected with Plasmodium berghei ANKA (PbA). Our results highlighted an immunomodulatory role of GFAP+ astrocytes underweening significant morphological and molecular alterations and adopting a unique intermediate reactivity state (A1/A2). This state was correlated with production of CXCL-10 and TGF-{beta}, which control inflammation without exacerbating infection. Our study also revealed a key role of the IL-33/ST2 pathway induced by Tg brain infection in protecting against ECM. Astrocyte-derived IL-33 was crucial to promote brain recruitment and activation of innate lymphoid cells (ILC2), which contribute to the hosts antiparasitic response. Additionally, we identified a distinctive intermediate M1/M2 phenotype in CD86+CD206+CD16/32+MHCIIhi microglia and noted an enhanced recruitment of inflammatory monocytes, both contributing to inflammation and control of PbA infection. This study reveals, for the first time, how latent brain infection with T. gondii confers protection against a severe cerebral form of malaria, positioning astrocytes at the core of the neuroinflammatory response that controls PbA infection severity. This expands our understanding of host-pathogen interactions and the potential for targeting astrocytic pathways in preventing CM. Author SummaryCerebral malaria (CM) is one of the most severe complications of Plasmodium infection, often leading to coma and death. The mechanisms that determine why some individuals develop this life-threatening condition remain poorly understood. In this study, we explored how a chronic brain infection with the parasite Toxoplasma gondii influences the development of CM in mice. We found that Tg infection reshapes the brains immune environment, particularly through the actions of astrocytes, cells that normally support and protect neurons. During coinfection, astrocytes adopted a balanced reactive state that limited inflammation without worsening the infection. This response involved the IL-33/ST2 signalling pathway and led to the recruitment of protective immune cells, helping to control Plasmodium infection in the brain. Our findings uncover an unexpected protective role of latent T. gondii infection and identify astrocytes as central regulators of neuroinflammation. This work highlights potential new strategies for preventing or mitigating cerebral malaria by targeting astrocyte-mediated immune responses.

immunology↗