Author(s): Gordino, Gisela ; Pereira, Sara ; Gomes, Anita Q. ; silva-Santos, Bruno ; Ribot, Julie
Date: 2019
Persistent ID: http://hdl.handle.net/10400.21/11308
Origin: Repositório Científico do Instituto Politécnico de Lisboa
Subject(s): Immune system; miR-181a; Cancer immunotherapy; T cell differentiation
Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent anti-tumor functions. importantly, we have previously shown that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells but could acquire those properties upon stimulation with IL-2 or IL-15. This notwithstanding, the role of post-transcriptional mechanisms mediated by miRs in the acquisition of the γδ Th1-like phenotype remains unclear. By resorting to RNA-sequencing techniques, we have identified a discrete repertoire of miRs associated with this process, highlighting miR-181a as a potential regulator of γδ T cell functional differentiation. Strikingly, we have observed that miR-181a expression in γδ T cells could be altered by the presence of anti-inflammatory or pro-inflammatory cytokines, either upregulating or downregulation this miR levels, respectively, thus evidencing his role in modulating pathological responses elicited by γδ T cells. Importantly, in a series of gain-of-function experiments, we verified that miR-181a overexpression significantly impaired NKG2D, TNF-α and IFN-γ expression in the Vδ1+ subpopulation. additionally, the RT-PCR analysis of those samples allowed us to verify a decrease in the mRNA levels of genes linked to the cytotoxic potential of these cells. By using luciferase reporter technology, we have been able to validate Map3k2 and Notch2 as direct targets, through which miR-181a elicits his impairment of the Th1-like phenotype in γδ T cells. These findings may have major implications for the manipulation of γδ T cells in cancer immunotherapy.
