Tight regulatory control of lymphocyte activation is necessary to avoid the deleterious consequences of an uncontrolled immune response. A complicated web of up-regulatory and down-regulatory processes governs a key activation pathway in lymphocytes, the antigen-receptor-to-NF-κB pathway; however, the complex interplay between positive and negative regulation of this pathway remains poorly understood. We have utilized cutting-edge super-resolution imaging technologies to examine the spatial and temporal organization of the POLKADOTS signalosome, which is inducibly formed in response to antigen stimulation of T lymphocytes. Our preliminary results suggest that this filamentous signalosome is divided into two distinct subregions: an activation domain which recruits signal transduction elements, and a downregulation domain which promotes macroautophagic degradation of the signalosome. Fixed and live cell imaging of the activation process indicates that POLKADOTS filaments converge on the microtubule-organizing center as the core filament protein Bcl10 is progressively degraded by autophagosomes. Furthermore, following Bcl10 degradation, the POLKADOTS components Malt1 and phospho-IKK are transferred to a peri-nuclear aggresomal structure. Surprisingly, our data suggest these aggresomal accumulations continue to promote NF-κB nuclear localization and T cell activation. Together, these results provide new insights into the complex regulatory processes which govern T lymphocyte activation, and for the first time suggest a signaling function for aggresomes.
Citation Format: Maria Traver, Leonard Campanello, Suman Paul, Wolfgang Losert, Hari Shroff, Brian Schaefer. Mechanisms of T lymphocyte activation revealed by super-resolution microscopy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B046.
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