Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes. Consequently, Sam68-ko Th1 cells are significantly impaired in IFN-γ production. Moreover, we found that Sam68 is required for the induction of an inflammatory Th1 response during Mycobacterium bovis Bacillus Calmette–Guerin (BCG) infection, thus limiting bacterial dissemination in the lungs. Mechanistically, Sam68 directly binds to the microRNA miR-29, a negative regulator of Th1 response, and inhibits its expression during BCG infection. These findings uncover a novel post-transcriptional mechanism required for the Th1-mediated defense against intracellular pathogens and identify a new function for Sam68 in the regulation of the immune response.
La polarizzazione delle cellule T naive in cellule T helper 1 (Th1) producenti interferone (IFN) -γ è un evento essenziale nella risposta infiammatoria ai patogeni. Qui, identifichiamo la proteina legante l'RNA Sam68 come un modulatore specifico della differenziazione Th1. I linfociti T naive knock-out (ko) di Sam68 sono fortemente difettosi nella polarizzazione Th1 mediata da IL-12 ed esprimono bassi livelli di T-bet ed Eomes. Di conseguenza, le cellule Th1 Sam68-ko sono significativamente compromesse nella produzione di IFN-γ. Inoltre, abbiamo scoperto che Sam68 è necessario per l'induzione di una risposta Th1 infiammatoria durante l'infezione da Mycobacterium bovis Bacillus Calmette-Guerin (BCG), limitando così la disseminazione batterica nei polmoni. Meccanicamente, Sam68 si lega direttamente al microRNA miR-29, un regolatore negativo della risposta Th1 e inibisce la sua espressione durante l'infezione da BCG. Questi risultati rivelano un nuovo meccanismo post-trascrizionale richiesto per la difesa mediata da Th1 contro i patogeni intracellulari e identifica una nuova funzione per Sam68 nella regolazione della risposta immunitaria.
The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29 / Volpe, Elisabetta; Cesari, Eleonora; Mercatelli, Neri; Cicconi, Rosella; De Bardi, Marco; Capone, Alessia; Bonvissuto, Davide; Fraziano, Maurizio; Mattei, Maurizio; Battistini, Luca; Paronetto, Maria Paola; Sette, Claudio. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - (2018). [10.1038/s41418-018-0201-9]
The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29
Capone, Alessia;BONVISSUTO, DAVIDE;
2018
Abstract
Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes. Consequently, Sam68-ko Th1 cells are significantly impaired in IFN-γ production. Moreover, we found that Sam68 is required for the induction of an inflammatory Th1 response during Mycobacterium bovis Bacillus Calmette–Guerin (BCG) infection, thus limiting bacterial dissemination in the lungs. Mechanistically, Sam68 directly binds to the microRNA miR-29, a negative regulator of Th1 response, and inhibits its expression during BCG infection. These findings uncover a novel post-transcriptional mechanism required for the Th1-mediated defense against intracellular pathogens and identify a new function for Sam68 in the regulation of the immune response.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
