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Biology subjects

Regnier, F.

Publications and source records attributed to Regnier, F..

3 recordsLinked to original sources

A protein kinase A-regulated centrosomal actin pool sets the threshold for T cell polarization

T lymphocyte migration triggered by chemokine stimulation is preceded by cell polarization. The acquisition of this asymmetry requires a profound cell rearrangement, particularly of the cytoskeleton. The mechanism by which a uniform signal triggered by chemokine receptors rapidly leads to this asymmetry is largely elusive. Using cell imaging, we emphasize that the centrosome dictates the position of the polarization axis in T lymphocytes. Mechanistically, we highlight that the T cell shape is controlled by the amount of actin filaments surrounding the centrosome. In resting conditions as well as after chemokine stimulation, the activity of a specific pool of protein kinase A regulates this cytoskeleton compartment. Once the centrosomal actin is reduced below a certain threshold, the symmetry breaking is catalyzed. This study points to a critical protein kinase A signaling pathway in the establishment of the immune response.

immunology↗

cAMP bursts control T cell directionality by actin cytoskeleton remodeling

T lymphocyte migration is an essential step to mounting an efficient immune response. The rapid and random motility of these cells which favors their sentinel role is conditioned by chemokines as well as by the physical environment. Morphological changes, underlaid by dynamic actin cytoskeleton remodeling, are observed throughout migration but especially when the cell modifies its trajectory. Using dynamic cell imaging, we investigated the signaling pathways involved in T cell directionality control. We monitored cAMP variation concomitantly with actin distribution upon T lymphocyte migration and highlighted the fact that spontaneous bursts in cAMP starting from the leading edge, are sufficient to promote stable actin redistribution triggering trajectory modification.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN/{beta} and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGF{beta}.

cancer biology↗