Murine regulatory T cells induce death of effector T, B, and NK lymphocytes through a contact-independent mechanism involving telomerase suppression and telomere-associated senescence

Autor: D. V. Grishin, Vladimir A. Grachev, M. V. Pokrovskaya, Nikolay N. Sokolov, D. D. Zhdanov, V. S. Orlova, Svetlana S. Alexandrova, Yulia A. Gladilina, Vadim S. Pokrovsky
Rok vydání: 2018
Předmět:
Zdroj: Cellular Immunology. 331:146-160
ISSN: 0008-8749
DOI: 10.1016/j.cellimm.2018.06.008
Popis: Regulatory T cells (Tregs) suppress the activity of effector T, B and NK lymphocytes and sustain immunological tolerance, but the proliferative activity of suppressed cells remains unexplored. In the present study, we report that mouse Tregs can induce replicative senescence and the death of responder mouse CD4+CD25- T cells, CD8+ T cells, B cells and NK cells in vitro and in vivo. Contact-independent in vitro co-cultivation with Tregs up-regulated endonuclease G (EndoG) expression and its translocation to the nucleus in responder cells. EndoG localization in the nucleus induced alternative mRNA splicing of the telomerase catalytic subunit Tert and telomerase inhibition. The lack of telomerase activity in proliferating cells led to telomere loss followed by the development of senescence and cell death. Injection of Tregs into mice resulted in EndoG-associated alternative splicing of Tert, telomerase inhibition, telomere loss, senescence development and increased cell death in vivo. The present study describes a novel contact-independent mechanism by which Tregs specify effector cell fate and provides new insights into cellular crosstalk related to immune suppression.
Databáze: OpenAIRE
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