Biology subjects

Fassett, M. S.

Publications and source records attributed to Fassett, M. S..

3 recordsLinked to original sources

bioRxiv2023

An essential role for miR-15/16 in Treg suppression and restriction of proliferation

The miR-15/16 family is a highly expressed group of tumor suppressor miRNAs that target a large network of genes in T cells to restrict their cell cycle, memory formation and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector T cells to mediate a sustained immune response. Here, using conditional deletion of miR-15/16 in immunosuppressive regulatory T cells (Tregs) that express FOXP3, we identify new functions of the miR-15/16 family in T cell immunity. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16-deficiency alters Treg expression of critical functional proteins including FOXP3, IL2R/CD25, CTLA4, PD-1 and IL7R/CD127, and results in accumulation of functionally impaired FOXP3loCD25loCD127hi Tregs. Excessive proliferation in the absence of miR-15/16 inhibition of cell cycle programs shifts Treg diversity and produces an effector Treg phenotype characterized by low expression of TCF1, CD25 and CD62L, and high expression of CD44. These Tregs fail to control immune activation of CD4+ effector T cells, leading to spontaneous multi-organ inflammation and increased allergic airway inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance. HighlightsO_LITreg-specific miR-15/16 expression is essential to prevent systemic tissue inflammation C_LIO_LImiR-15/16 restrict Treg proliferation and regulate expression of the key functional Treg molecules FOXP3, IL2R, CTLA4, PD-1 and IL7R C_LIO_LImiR-15/16 limit formation of effector Tregs and is necessary for high suppressive capacity C_LI

molecular biology↗

bioRxiv2021

IL-31 uncouples skin inflammation from itch sensation in allergic dermatitis

Despite a robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and on the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the effects of IL-31 and its receptor IL31RA on both inflammation and pruritus in mouse models of dermatitis, including chronic topical house dust mite (HDM) exposure. Unexpectedly, Il31 deficiency increased cutaneous adaptive type 2 cytokine-producing cells and serum IgE. In addition, M2-like macrophages capable of fueling feedforward pro-inflammatory loops were selectively enriched in Il31ra-deficient skin. Thus, IL-31 is not strictly a pro-inflammatory cytokine, but rather an immunoregulatory factor that limits the magnitude of allergic skin inflammation. In contrast, Il31-deficient mice displayed a deficit in HDM-induced scratching. Itch reduction occurred despite intact - and in some cases increased - responsiveness of sensory neurons to other pruritogens released during HDM challenge, highlighting the non-redundant contribution of IL-31-receptive sensory afferents to pruritus in environmental allergen-induced dermatitis. When present, therefore, IL-31 uncouples circuits driven by sensory neurons and immune cells that converge in inflamed skin.

immunology↗

bioRxiv2021

Type 2 innate immunity regulates hair follicle homeostasis to control Demodex pathosymbionts

Allergic skin diseases are common, but basal roles for type 2 immunity in cutaneous homeostasis are incompletely understood. Here, we show that skin group 2 innate lymphoid cells (ILC2s) are the predominant resident cells that secretes IL-13, which attenuates epithelial cell proliferation during anagen throughout the hair follicle (HF), including in HF stem cells. Although HF are normal in the absence of type 2 immunity, colonization with the commensal mite, Demodex musculi, results in epithelial proliferation and aberrant hair follicle morphology accompanied by loss of stable commensalism with massive infestation and expansion of inflammatory ILC2s and other immune cells. Topical anti-parasitic agents, but not broad-spectrum antibiotics, reversed the phenotype. Commensal Demodex colonization of mammalian hair follicles is ubiquitous, including in humans, revealing an unanticipated role for ILC2s and type 2 immunity for skin homeostasis in the normal environment. One Sentence SummaryDynamic regulation of skin physiology by Type 2 innate immunity regulates healthy commensalism by parasitic Demodex mites.

immunology↗