Biology subjects

Grencis, R.

Publications and source records attributed to Grencis, R..

3 recordsLinked to original sources

bioRxiv2026

IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity

Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.

immunology↗

bioRxiv2022

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses

Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from the diet, commensal microbiota and invading pathogens - most notably helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient and metabolite availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters impaired ILC2 expansion, but not cytokine production, in part via tuning of mTOR activation. These findings implicate the import of amino acids as a metabolic requisite for optimal ILC2 responses, and further highlight nutritional cues as critical regulators of innate immune responses within mucosal barrier tissues.

immunology↗

bioRxiv2020

T-bet fate mapping identifies a novel ILC1-ILC2 subset in vivo

Innate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Various subsets exist resembling T cell lineages defined by the expression of specific transcription factors. Thus, T-bet is expressed in ILC1 and Th1 cells. In order to further understand the functional roles of T-bet in ILC, we generated a fate-mapping mouse model that permanently marks cells and their progeny that are expressing, or have ever expressed T-bet. Here we have identified and characterised a novel ILC with characteristics of ILC1 and ILC2 that are "fate-mapped" for T-bet expression and arise early in neonatal life prior to establishment of a mature microbiome. These ILC1-ILC2 cells are critically dependent on T-bet and are able to express type 1 and type 2 cytokines at steady state, but not in the context of inflammation. These findings refine our understanding of ILC lineage regulation and stability and have important implications for the understanding of ILC biology at mucosal surfaces. SUMMARYInnate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Three distinct ILC groups have been described according to expression of subset defining transcription factors and other markers. In this study we characterize a novel ILC subset with characteristics of group 1 and group 2 ILC in vivo.

immunology↗