PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs.

Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell-mediated immune responses. Blocking such signaling provides the clinical effects of PD-1-targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1-mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1 engagement on actin remodeling at the immunological synapse, the interface between a T cell and an antigen-presenting cell (APC) or target cell. We used microscopy to analyze the formation of immunological synapses between PD-1+ Jurkat cells or primary human CD8+ cytotoxic T cells and APCs that presented T cell-activating antibodies and were either positive or negative for PD-L1. PD-1 binding to PD-L1 inhibited T cell spreading induced by antibody-mediated activation, which was characterized by the absence of the F-actin-dense distal lamellipodial network at the immunological synapse and the Arp2/3 complex, which mediates branched actin formation. PD-1-induced inhibition of actin remodeling also prevented the characteristic deformation of T cells that contact APCs and the release of cytotoxic granules. We showed that the effects of PD-1 on actin remodeling did not require its tyrosine-based signaling motifs, which are thought to mediate the co-inhibitory effects of PD-1. Our study highlights a previously unappreciated mechanism of PD-1-mediated suppression of T cell activity, which depends on the regulation of actin cytoskeleton dynamics in a signaling motif-independent manner.

RELA tunes innate-like interferon I/III responses in human T cells.

In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.

[Combining CAR-T cells anti-tumoral activity with exosomes properties: an innovative approach to fight cancer]. / Allier les capacités anti-tumorales des CAR-T cells aux propriétés des exosomes : une approche innovante pour combattre le cancer - L'actualité scientifique vue par les étudiants du Master 2 « Immunologie Translationnelle et Biothérapies ¼ (ITB) et « Immunologie Intégrative et Systémique ¼ (I2S) (Mention Biologie Moléculaire et Cellulaire, Parcours Immunologie, Sorbonne Université).

TITLE: Allier les capacités anti-tumorales des CAR-T cells aux propriétés des exosomes : une approche innovante pour combattre le cancer. ABSTRACT: Dans le cadre de leur module d'analyse scientifique, des étudiants de la promotion 2019-2020 des Master 2 « Immunologie Translationnelle et Biothérapies ¼ (ITB) et « Immunologie Intégrative et Systémique ¼ (I2S) (Mention Biologie Moléculaire et Cellulaire, Parcours Immunologie, Sorbonne Université) se sont penchés sur la littérature et ont pris la plume pour partager avec les lecteurs de m/s quelques-uns des faits marquants de l'actualité en immunologie. On y découvre ainsi les nouvelles avancées dans l'optimisation des immunothérapies à base de CAR T (thérapie cellulaire), mais également les résultats de travaux portant sur le rôle du stress ou du métabolisme sur les réponses immunitaires, et enfin des données très intéressantes sur l'impact du microbiote sur l'homéostasie du système immunitaire et la réponse aux vaccins. Plusieurs articles soulignent ainsi l'importance de la communication entre le système immunitaire et d'autres grandes fonctions physiologiques de l'organisme, en particulier le système hormonal et le métabolisme, et mettent ainsi en évidence l'intérêt d'avoir une analyse intégrative des réponses immunitaires.