ISG20L2, a 3' to 5' exoribonuclease previously associated with ribosome biogenesis, is identified here in activated T cells as an enzyme with a preferential affinity for uridylated miRNA substrates. This enzyme is upregulated in T lymphocytes upon TCR and IFN type I stimulation and appears to be involved in regulating T cell function. ISG20L2 silencing leads to an increased basal expression of CD69 and induces greater IL2 secretion. However, ISG20L2 absence impairs CD25 upregulation, CD3 synaptic accumulation and MTOC translocation towards the antigen-presenting cell during immune synapsis. Remarkably, ISG20L2 controls the expression of immunoregulatory molecules, such as AHR, NKG2D, CTLA-4, CD137, TIM-3, PD-L1 or PD-1, which show increased levels in ISG20L2 knockout T cells. The dysregulation observed in these key molecules for T cell responses support a role for this exonuclease as a novel RNA-based regulator of T cell function.

Bioinformatics Unit Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

Cardiovascular Proteomics Laboratory Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 A35 625 00 Brno Czech Republic

Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares Madrid Spain

Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Instituto Investigación Sanitaria Princesa Madrid Spain

Intercellular Communication in the Inflammatory Response Vascular Pathophysiology Area Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

Universidad Autónoma de Madrid Madrid Spain

Universidad Complutense de Madrid Madrid Spain

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