How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4+ T cell quiescence. LINE1-containing transcripts are derived from CD4+ T cell-specific genes upregulated during T cell activation. In naive CD4+ T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.

Marasca, F., Sinha, S., Vadalà, R., Polimeni, B., Ranzani, V., Paraboschi, E., et al. (2022). LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion. NATURE GENETICS, 54(2), 180-193 [10.1038/s41588-021-00989-7].

LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion

Vadalà, Rebecca;Polimeni, Benedetto;Ranzani, Valeria;Harari, Sergio;
2022

Abstract

How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4+ T cell quiescence. LINE1-containing transcripts are derived from CD4+ T cell-specific genes upregulated during T cell activation. In naive CD4+ T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.
Articolo in rivista - Articolo scientifico
LINE1; TILs;
English
180
193
14
Marasca, F., Sinha, S., Vadalà, R., Polimeni, B., Ranzani, V., Paraboschi, E., et al. (2022). LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion. NATURE GENETICS, 54(2), 180-193 [10.1038/s41588-021-00989-7].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/348980
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