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Transcriptome and Chromatin Landscape of iNKT cells are Shaped by Subset Differentiation and Antigen Exposure [ATAC-seq]

ABSTRACT: Invariant natural killer T cells (iNKT cells) differentiate into thymic NKT1, NKT2 and NKT17 subsets that are also peripheral. We determined if the gene programs associated with these thymic subsets were maintained in peripheral sites, the influence of tissue location, and if there were large-scale changes after antigen exposure. RNA-seq and ATAC-seq analyses showed that iNKT cells in any subset were similar, regardless of tissue location. Lung iNKT cell subsets shared the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. After antigenic stimulation, iNKT cells underwent chromatin and transcription changes leading to two populations: one similar to follicular helper T cells and the other like NK cells. Phenotypic analysis indicated these changes were observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to several new subsets.

ORGANISM(S): Mus musculus

PROVIDER: GSE161491 | GEO | 2021/01/26

REPOSITORIES: GEO

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Transcriptome and Chromatin Landscape of iNKT Cells are Shaped by Subset Differentiation and Antigen Exposure [RNA-seq]

Project description:Invariant natural killer T cells (iNKT cells) differentiate into thymic NKT1, NKT2 and NKT17 subsets that are also peripheral. We determined if the gene programs associated with these thymic subsets were maintained in peripheral sites, the influence of tissue location, and if there were large-scale changes after antigen exposure. RNA-seq and ATAC-seq analyses showed that iNKT cells in any subset were similar, regardless of tissue location. Lung iNKT cell subsets shared the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. After antigenic stimulation, iNKT cells underwent chromatin and transcription changes leading to two populations: one similar to follicular helper T cells and the other like NK cells. Phenotypic analysis indicated these changes were observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to several new subsets.

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Project description:Functional subsets of iNKT cells, NKT1, NKT2 and NKT17, have been reported to arise during the thymus to peripheral differentiation stages. The key transcription factors for NKT1, NKT2 and NKT17 development in the thymus have been identified as T-bet, Gata3 and Rorγt, respectively. In contrast, these iNKT cell subsets can also undergo further differentiation in the periphery. Eomesodermin (Eomes) is a T-box transcription factor with high homology to T-bet and is expressed by activated CD8+ T cells as well as in resting and activated NK cells. However, its role in invariant (i)NKT cells remains unknown. Here, we show the impact of Eomes on iNKT cells in the thymus and peripheral tissue using conditional knockout (Eomes-cKO) mice. Eomes regulates the differentiation of NKT1 cells in the thymus. In the peripheral tissue, Klrg1+ iNKT1 cells are generated in lung after vaccination with -GalCer-pulsed DCs (DC/Gal) as memory like iNKT cells. In the current study, we found that Eomes also regulates their differentiation into memory-like KLRG1+iNKT cells in the periphery.

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