Cross-talk between CD8+ T cells and natural killers: the role of mitochondrial Aa2+ transport
© Uzhachenko et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Unraveling complex interactions between immune cells is a key to the development of new strategies for immunotherapy. In the present study, we investigated functional outcome of bidirectional interaction between activated CD8+T and naive natural killer (NK) cells. We found that phorbol 12-myristate 13-acetate (PMA)/Ionomycin (Io)-stimulated CD8+T cells form multiple intercellular contacts with naive NK lymphocytes. Co-culture of activated T cells with naïve NK cells results in the selective down-regulation of CD25 molecule in T cells while elevating CD25 and CD69 expression on naive NK cells. Further, CD8+T and NK cells cross-regulate mitochondrial homeostasis including calcium transport. This effect is dependent on both cytokines and intercellular contacts, and partially involves natural killer group 2 member D (NKG2D) receptor activation. Data also suggest that activated CD8+T cells might directly transfer mitochondria and activation molecules such as CD25 and CD69 to naive NK cells. Alterations in phosporylation status of multiple signaling proteins during CD8+T/NK interaction suggest a functional remodeling whereby NK cells shift activated CD8+T cells towards T central-memory (TCM) phenotype and activated CD8+T lymphocytes alter naive state of NK cells towards effector/regulatory phenotype. Inhibition of mitochondrial Ca2+ uptake (mCU) or Na+/Ca2+ exchanger (mNCE) with Ru360 and CGP37157 respectively mimicked observed alterations in CD8+ and NK cells upon their interaction. These data suggest a potential role of mitochondrial Ca2+ homeostasis in the acquisition of mixed activation/regulatory phenotype by NK cells during T cell-NK cell interaction. We believe that understanding the mechanisms of CD8+-NK interplay will help to develop new approaches for cellular immunotherapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.