mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2012-1-2-43-50mimmun-294Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESХАРАКТЕРИСТИКА СИГНАЛЬНЫХ ПУТЕЙ, ОПОСРЕДУЮЩИХ ЦИТОТОКСИЧЕСКИЙ ЭФФЕКТДЕНДРИТНЫХ КЛЕТОК ПРОТИВ АКТИВИРОВАННЫХ Т-ЛИМФОЦИТОВ И NK-КЛЕТОКCHARACTERISTICS OF SIGNALING PATHWAYS MEDIATING A CYTOTOXIC EFFECT OF DENDRITIC CELLS UPON ACTIVATED Т LYMPHOCYTES AND NK CELLSТыриноваТ. В.TyrinovaT. V.

630099, Новосибирск, ул. Ядринцевская, 14. Тел.: (383) 236-03-29.

ct_lab@mail.ruЛеплинаО. Ю.LeplinaO. Yu.ct_lab@mail.ruТихоноваМ. А.TikhonovaM. A.ct_lab@mail.ruСахноЛ. В.SakhnoL. V.ct_lab@mail.ruОстанинА. А.OstaninA. A.ct_lab@mail.ruЧерныхЕ. Р.ChernykhE. R.ct_lab@mail.ruНИИ клинической иммунологии СО РАМНRussian Federation201219072014141-24350Copyright © Тыринова Т.В., Леплина О.Ю., Тихонова М.А., Сахно Л.В., Останин А.А., Черных Е.Р., 20142014Тыринова Т.В., Леплина О.Ю., Тихонова М.А., Сахно Л.В., Останин А.А., Черных Е.Р.Tyrinova T.V., Leplina O.Y., Tikhonova M.A., Sakhno L.V., Ostanin A.A., Chernykh E.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/294

Abstract. Cytotoxic/pro-apoptogenic effects of IFNα-induced dendritic cells (IFN-DCs) directed against Т-lymphocytes and NK cells were investigated in healthy donors. Using an allogenic MLC system, it was revealed that IFN-DCs induce apoptosis of both activated CD4+ and CD8+ T-lymphocytes, and NK cells. Apoptosis of CD4+ and CD8+ T-lymphocytes induced by their interaction with IFN-DCs was mediated by various signaling pathways. In particular, activated CD4+Т-lymphocytes were most sensitive to TRAIL- и Fas/ FasL-transduction pathways, whereas activated CD8+ T-lymphocytes were induced to apoptosis via TNFα-mediated pathway. PD-1/B7-H1-signaling pathway also played a distinct role in cytotoxic activity of IFNDCs towards both types of T lymphocytes and activated NK cells. The pro-apoptogenic/cytotoxic activity of IFN-DC against activated lymphocytes may be regarded as a mechanism of a feedback regulation aimed at restriction of immune response and maintenance of immune homeostasis. Moreover, upregulation of proapoptogenic molecules on DCs under pathological conditions may lead to suppression of antigen-specific response, thus contributing to the disease progression.

дендритные клеткиTRAILFasLB7-H1/PD-1Т-лимфоцитыNK-клеткиапоптозdendritic cellsTRAILFasLB7-H1/PD-1Т-lymphocytesNK-cellsapoptosisГрант ФЦП «Научные и научно-педагогические кадры инновационной России» (госконтракт № 14.740.11.0007) и грант РФФИ № 10-04-00280ReferencesЛеплина О.Ю., Тыринова Т.В., Ступак В.В., Мишинов С.В., Пендюрин И.В., Останин А.А., Черных Е.Р. Эффекторные функции интерферон-α-индуцированных дендритных клеток у здоровых доноров и больных опухолями головного мозга // Российский иммунологический журнал. – 2011. (в печати)Леплина О.Ю., Тыринова Т.В., Ступак В.В., Мишинов С.В., Пендюрин И.В., Останин А.А., Черных Е.Р. Эффекторные функции интерферон-α-индуцированных дендритных клеток у здоровых доноров и больных опухолями головного мозга // Российский иммунологический журнал. – 2011. (в печати)Сахно Л.В., Тихонова М.А., Леплина О.Ю., Тыринова Т.В., Никонов С.Д., Жданов О.А., Останин А.А., Черных Е.Р. Роль PD-1/ B7-H1-опосредованного пути в нарушении антигенспецифического ответа у больных туберкулезом легких // Иммунология. – 2011. – № 2. – С. 89-95.Сахно Л.В., Тихонова М.А., Леплина О.Ю., Тыринова Т.В., Никонов С.Д., Жданов О.А., Останин А.А., Черных Е.Р. Роль PD-1/ B7-H1-опосредованного пути в нарушении антигенспецифического ответа у больных туберкулезом легких // Иммунология. – 2011. – № 2. – С. 89-95.Селедцова Н.В., Хонина Н.А., Тихонова М.А., Останин А.А., Пасман Н.М., Черных Е.Р. Влияние дегидроэпиандростерона сульфата на фенотип и функции дендритных клеток in vitro // Мед. иммунология. – 2007. – Т. 9, № 6. – С. 589-596.Селедцова Н.В., Хонина Н.А., Тихонова М.А., Останин А.А., Пасман Н.М., Черных Е.Р. Влияние дегидроэпиандростерона сульфата на фенотип и функции дендритных клеток in vitro // Мед. иммунология. – 2007. – Т. 9, № 6. – С. 589-596.Belkaid Y., Oldenhove G. Tuning microenvironments: induction of regulatory T cells by dendritic cells // Immunity. – 2008. – Vol. 29. – P. 362-371.Belkaid Y., Oldenhove G. Tuning microenvironments: induction of regulatory T cells by dendritic cells // Immunity. – 2008. – Vol. 29. – P. 362-371.Bosque A., Pardo J., Martinez-Lorenzo M.J., Lasierra P., Larrad L., Marzo I., Naval J., Anel A. Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL // Eur. J. Immunol. – 2005. – Vol. 35. – P. 1812-1821.Bosque A., Pardo J., Martinez-Lorenzo M.J., Lasierra P., Larrad L., Marzo I., Naval J., Anel A. Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL // Eur. J. Immunol. – 2005. – Vol. 35. – P. 1812-1821.Buonocore S., Haddou N.O., Moore F., Florquin S., Paulart F., Heirman C., Thielemans K., Goldman M., Flamand V. Neutrophil-dependents // FEBS Lett. – 1993. – Vol. 319. – P. 80-83. tumor rejection and priming of tumoricidal CD8+ Tcell response induced by dendritic cells overexpressing CD95L // J. Leukoc. Biol. – 2008. – Vol. 84. – P. 713-720.Buonocore S., Haddou N.O., Moore F., Florquin S., Paulart F., Heirman C., Thielemans K., Goldman M., Flamand V. Neutrophil-dependents // FEBS Lett. – 1993. – Vol. 319. – P. 80-83. tumor rejection and priming of tumoricidal CD8+ Tcell response induced by dendritic cells overexpressing CD95L // J. Leukoc. Biol. – 2008. – Vol. 84. – P. 713-720.Chauvin C., Josien R. Dendritic сells as killers: mechanistic aspects and potential roles // J. Immunol. – 2008. – Vol. 181. – P. 11-16.Chauvin C., Josien R. Dendritic сells as killers: mechanistic aspects and potential roles // J. Immunol. – 2008. – Vol. 181. – P. 11-16.Dudley E., Hornung F., Zheng L., Scherer D., Ballard D., Lenardo M. NF-kappaB regulates Fas/ APO-1/CD95- and TCR-mediated apoptosis of T lymphocytes // Eur. J. Immunol. – 1999. – Vol. 29. – P. 878-886.Dudley E., Hornung F., Zheng L., Scherer D., Ballard D., Lenardo M. NF-kappaB regulates Fas/ APO-1/CD95- and TCR-mediated apoptosis of T lymphocytes // Eur. J. Immunol. – 1999. – Vol. 29. – P. 878-886.Hoves S., Krause S.W., Herfarth H., Halbritter D., Zhang H.G., Mountz J.D., Scholmerich J., Fleck M. Elimination of activated but not resting primary human CD4+ and CD8+T cells by Fas ligand (FasL/CD95L)-expressing killer-dendritic cells // Immunobiology. – 2004. – Vol. 208. – P. 463-475.Hoves S., Krause S.W., Herfarth H., Halbritter D., Zhang H.G., Mountz J.D., Scholmerich J., Fleck M. Elimination of activated but not resting primary human CD4+ and CD8+T cells by Fas ligand (FasL/CD95L)-expressing killer-dendritic cells // Immunobiology. – 2004. – Vol. 208. – P. 463-475.Janjic B.M., Lu G., Pimenov A., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate direct anticancer effector function of human immature dendritic cells. I. Involvement of an apoptosis-inducing pathway // J. Immunol. – 2002. – Vol. 168. – P. 1823-1830.Janjic B.M., Lu G., Pimenov A., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate direct anticancer effector function of human immature dendritic cells. I. Involvement of an apoptosis-inducing pathway // J. Immunol. – 2002. – Vol. 168. – P. 1823-1830.Kim S.H., Bianco N., Menon R., Lechman E.R., Shufesky W.J., Morelli A.E., Robbins P.D. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive // Mol. Ther. – 2006. – Vol. 13. – P. 289-300.Kim S.H., Bianco N., Menon R., Lechman E.R., Shufesky W.J., Morelli A.E., Robbins P.D. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive // Mol. Ther. – 2006. – Vol. 13. – P. 289-300.Langlois R.A., Legge K.L. Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T-cells // J. Immunol. – 2010. – Vol. 184. – P. 4440-4446.Langlois R.A., Legge K.L. Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T-cells // J. Immunol. – 2010. – Vol. 184. – P. 4440-4446.Lu G., Janjic B.M., Janjic J., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, lymphotoxin-α1β2, Fas ligand, and TNF-related apoptosis-inducing ligand // J. Immunol. – 2002. – Vol. 168. – P. 1831-1839.Lu G., Janjic B.M., Janjic J., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, lymphotoxin-α1β2, Fas ligand, and TNF-related apoptosis-inducing ligand // J. Immunol. – 2002. – Vol. 168. – P. 1831-1839.Rissoan M.C., Duhen T., Wesa A.K., Storkus W.J. Killer dendritic cells: mechanisms of action and therapeutic implications for cancer // Cell Death Differ. – 2008. – Vol. 15. – P. 51-57.Rissoan M.C., Duhen T., Wesa A.K., Storkus W.J. Killer dendritic cells: mechanisms of action and therapeutic implications for cancer // Cell Death Differ. – 2008. – Vol. 15. – P. 51-57.Sharpe A.H., Wherry E.J., Ahmed R., Freeman G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection // Nature Immunology. – 2007. – Vol. 8. – P. 239-245.Sharpe A.H., Wherry E.J., Ahmed R., Freeman G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection // Nature Immunology. – 2007. – Vol. 8. – P. 239-245.Stary G., Klein I., Kohlhofer S., Koszik F., Scherzer T., Mullauer L., Quendler H., Kohrgruber N., Stingl G. Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients // Blood. – 2009. – Vol. 114. – P. 3854-3863.Stary G., Klein I., Kohlhofer S., Koszik F., Scherzer T., Mullauer L., Quendler H., Kohrgruber N., Stingl G. Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients // Blood. – 2009. – Vol. 114. – P. 3854-3863.Waaga-Gasser A., Grimm M., Kim M., Rosenwald A., Germer C. T., Gasser M. Use of tumor-mediated TRAIL-receptor expression to evaluate apoptotic depletion of infiltrating CD8+immune cells in clinical colorectal cancer // J. Clin. Oncol. – 2010. – Vol. 28, N 15 (Suppl. 1). – abstr. E21038.Waaga-Gasser A., Grimm M., Kim M., Rosenwald A., Germer C. T., Gasser M. Use of tumor-mediated TRAIL-receptor expression to evaluate apoptotic depletion of infiltrating CD8+immune cells in clinical colorectal cancer // J. Clin. Oncol. – 2010. – Vol. 28, N 15 (Suppl. 1). – abstr. E21038.Wolfe T., Asseman C., Hughes A., Matsue H., Takashima A., von Herrath M.G. Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection // J. Immunol. – 2002. – Vol. 169. – P. 4867-4872.Wolfe T., Asseman C., Hughes A., Matsue H., Takashima A., von Herrath M.G. Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection // J. Immunol. – 2002. – Vol. 169. – P. 4867-4872.

The authors declare that there are no conflicts of interest present.