Beatrice Bodega, PhD
INGM, Istituto Nazionale di Genetica Molecolare, Milan, Italy
Department of Biosciences, University of Milan, Milan, Italy
How gene expression is controlled to preserve human T-cell quiescence is poorly understood. We discovered that LINE1 transposable elements are spliced in novel transcripts to enforce naïve T-cell quiescence. LINE1-transcripts derive from CD4+-specific genes upregulated during T-cell activation. In naïve CD4+ T-cells, LINE1-transcripts are regulated by the transcription factor IRF4 and kept at chromatin by Nucleolin; they act in cis, hampering H3K36me3 levels and stalling gene expression. T-cell differentiation induces LINE1-transcript downregulation by PTBP1 splicing suppressor and promotes expression of the corresponding protein-coding genes by GTF2F1 elongating factor through mTORC1. Dysfunctional T-cells, exhausted in vitro or tumor-infiltrating lymphocytes, accumulate LINE1-transcripts at chromatin. Remarkably, depletion of LINE1-transcripts restores TIL effector function.
We introduce LINE1-transcripts as the first of a new class of epigenetic immunoregulatory molecules that enforce the quiescence of naïve T lymphocytes controlling chromatin organization and thus the expression of fundamental genes for T-cell function.