• Natasja A M Kragten, Felix M Behr, Felipe A Vieira Braga, RemmerswaalEster B MEBMDept of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.Renal Transplant Unit, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Thomas H Wesselink, Anna E Oja, Pleun Hombrink, Axel Kallies, van LierRene A WRAWDept of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Regina Stark, and Klaas P J M van Gisbergen.
• Dept of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
• Eur. J. Immunol. 2018 Oct 1; 48 (10): 1644-1662.

AbstractCD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue-resident memory CD8 T cells (Trm) and circulating CD45RA+ effector-type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp-1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear. We examined the expression regulation of Hobit and Blimp-1 in murine and human CD8 T-cells to determine their timeframe of activity. While Blimp-1 mRNA was expressed throughout effector and memory T cells, Blimp-1 protein, was only transiently expressed during the effector stage. In contrast, Hobit mRNA and protein expression was stably maintained during quiescence, but downregulated after activation. Notably, Blimp-1 was required for expression of granzyme B in murine effector T cells and Trm, while Hobit specifically regulated granzyme B in murine Trm during the memory phase. These findings suggest that Blimp-1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment-ready modus in Trm.© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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