Biology subjects

Nadjsombati, M. S.

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

3 recordsLinked to original sources

bioRxiv2022

Genetic mapping reveals Pou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differential Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens. One Sentence SummaryGenetic mapping identifies Pou2af2 isoform usage as a novel regulator of tuft cell differentiation that tunes intestinal innate type 2 immunity.

immunology↗

bioRxiv2021

Ubiquitin specific protease 1 expression and function in T cell immunity

T cells are essential mediators of the immune responses against infectious diseases and provide long-lived protection from reinfection. The differentiation of naive T cells to effector T cells and subsequent differentiation and persistence of memory T cell populations in response to infection is a highly regulated process. E protein transcription factors and their inhibitors, Id proteins, are important regulators of both CD4+ and CD8+ T cell responses; however, their regulation at the protein level has not been explored. Recently, the deubiquitinase USP1 was shown to stabilize Id2 and modulate cellular differentiation in osteosarcomas. Here, we investigated a role for Usp1 in posttranslational control of Id2 and Id3 in T cells. We show that Usp1 was upregulated in T cells following activation in vitro or following infection in vivo, and the extent of Usp1 expression correlated with the degree of T cell expansion. Usp1 directly interacted with Id2 and Id3 following T cell activation. However, Usp1-deficiency did not impact Id protein abundance in effector T cells or alter effector CD8+ T cell expansion or differentiation following a primary infection. Usp1 deficiency did result in a gradual loss of memory cells over time and impaired accumulation and altered differentiation following a secondary infection. Together, these results identify Usp1 as a player in modulating recall responses at the protein level and highlight differences in regulation of T cell responses between primary and subsequent infection encounters. Finally, our observations reveal that differential regulation of Id2/3 proteins between immune vs non-immune cell types.

immunology↗

bioRxiv2018

Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

Initiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis secretes succinate as a metabolite, and sensing of both succinate and N. brasiliensis requires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

immunology↗