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.This study was supported by grant P2022/BMD7209-
INTEGRAMUNE from the Comunidad de Madrid, a grant from “La
Caixa” Banking Foundation (HR17-00016) to FS-M; the Spanish
Ministerio de Ciencia e Innovación (PDC2021-121719-I00 and PID2020-120412RB-I00 to FS-M), grant from AECC, CIBER Cardiovascular (CB16/11/00272, Fondo de Investigación Sanitaria del Instituto
de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo
Regional FEDER). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy
and Competitiveness (MINECO) and the Pro-CNIC Foundation, and
is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-
0505). Vaňáčová’s laboratory is supported by the Czech Science Foundation (20-19617S and 23-07372S to S.V.) and the institutional support
CEITEC 2020 (LQ1601). ARG and SGD are supported by a grant from the Spanish Ministry of Universities. Funding agencies do not
have intervened in the design of the studies, with no copyright over
the study.S
