mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-4-653-660mimmun-1715Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESСИГНАЛИНГ ЧЕРЕЗ РЕЦЕПТОР К ФАКТОРУ РОСТА ЭНДОТЕЛИЯ СОСУДОВ 1-ГО ТИПА КАК НОВЫЙ МЕХАНИЗМ ПОДАВЛЕНИЯ Т-КЛЕТОК ПРИ ОПУХОЛЕВОМ НЕОАНГИОГЕНЕЗЕVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1 SIGNALING AS A NOVEL MECHANISM OF T CELL SUPPRESSION IN TUMOR NEOANGIOGENESISЧерныхЕ. Р.ChernykhE. R.

д.м.н., профессор, член-корр. РАН, заведующая лабораторией клеточной иммунотерапии

630099, Россия, г. Новосибирск, ул. Ядринцевская, 14

Тел.: 8 (383) 236-03-29Факс: 8 (383) 222-70-28

PhD, MD, Professor (Medicine), Corresponding Member, Russian Academy of Sciences, Head, Laboratory of Cellular Immunotherapy

630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., 14

Phone: 7 (383) 236-03-29Fax: 7 (383) 222-70-28

ct_lab@mail.ruЛеплинаО. Ю.LeplinaO. Yu.

д.м.н., ведущий научный сотрудник, лаборатория клеточной иммунотерапии

630099, Россия, г. Новосибирск, ул. Ядринцевская, 14

PhD, MD (Medicine), Leading Research Associate, Laboratory of Cellular Immunotherapy

630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., 14

ct_lab@mail.ruТихоноваМ. А.TikhonovaM. A.

к.б.н., старший научный сотрудник, лаборатория клеточной иммунотерапии

630099, Россия, г. Новосибирск, ул. Ядринцевская, 14

PhD (Biology), Senior Research Associate, Laboratory of Cellular Immunotherapy

630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., 14

ct_lab@mail.ruБаторовЕ. В.BatorovE. V.

к.м.н., научный сотрудник лаборатории клеточной иммунотерапии

630099, Россия, г. Новосибирск, ул. Ядринцевская, 14

PhD (Medicine), Research Associate, Laboratory of Cellular Immunotherapy

630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., 14

ct_lab@mail.ruОстанинА. А.OstaninA. A.

д.м.н., профессор, главный научный сотрудник, лаборатория клеточной иммунотерапии

630099, Россия, г. Новосибирск, ул. Ядринцевская, 14

PhD, MD, Professor (Medicine), Main Research Associate, Laboratory of Cellular Immunotherapy

630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., 14

ostanin62@mail.ruФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»РоссияResearch Institute of Fundamental and Clinical ImmunologyRussian Federation201911032019214препринт653660Copyright © Черных Е.Р., Леплина О.Ю., Тихонова М.А., Баторов Е.В., Останин А.А., 20192019Черных Е.Р., Леплина О.Ю., Тихонова М.А., Баторов Е.В., Останин А.А.Chernykh E.R., Leplina O.Y., Tikhonova M.A., Batorov E.V., Ostanin A.A.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/1715

Выявление иммуномодулирующей активности факторов роста эндотелия сосудов (VEGFs) раскрывает новую роль неоангиогенеза в опухолевой прогрессии. Большинство эффектов VEGF на Т-клетки опосредуется через рецепторы VEGF-R2. Фактор роста плаценты (PlGF) принадлежит к семейству VEGFs и является селективным лигандом VEGF-R1. С целью изучения роли VEGF-R1-сигналинга в регуляции Т-клеточных функций исследовали влияние  PlGF на пролиферацию Т-клеток доноров. Показано, что PlGF в широком диапазоне доз ингибирует пролиферацию Т-лимфоцитов в культурах анти-CD3-стимулированных мононуклеарных клеток, подавляя пролиферативный ответ как CD4+ так и CD8+ Т-клеток. При этом супрессорный эффект PlGF обусловлен прямым взаимодействием фактора с VEGFR-1 на Т-клетках, что подтверждается экспрессией VEGFR-1 Т-лимфоцитами (особенно после их активации) и блокированием супрессорного эффекта PlGF нейтрализующими анти-VEGFR-1 антителами. Учитывая повышенный уровень PlGF при многих опухолях, данный фактор может играть важную роль в иммуномодуляции при опухолевом росте, опосредуя свой эффект через VEGFR-1 сигнальный путь.

The immunomodulatory activity of vascular endothelial growth factors (VEGFs) reveals a new role of neoangiogenesis in tumor development. Most of VEGF effects on T cells are mediated through the VEGF-R2 receptors. Placental growth factor (PlGF) belongs to the VEGFs family and is a selective ligand for VEGF-R1. In order to study the role of VEGF-R1-signaling in the regulation of T-cell functions, the effect of PlGF on the proliferation of donor T cell has been investigated. PlGF has been shown to inhibit the proliferation of T-lymphocytes in cultures of anti-CD3-stimulated mononuclear cells in a wide dose range, suppressing the proliferative response of both CD4 + and CD8 + T cells. The suppressive effect of PlGF was mediated through the direct interaction with VEGFR-1 on T-cells that was evidenced by the expression of VEGFR-1 by T-lymphocytes (especially after their activation) and by blocking the suppressive effect of PlGF with neutralizing anti-VEGFR-1 antibodies. Given the increased levels of PlGF in many tumors, this factor may play an important role in immunomodulation during tumor growth, mediating its effect through the VEGFR-1 signaling pathway.

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Biol., 2007, Vol. 82, no. 6, pp. 1473-2480.Lin Y-L, Liang Y-C, Chiang B-L. Placental growth factor down-regulates type 1 T helper immune response by modulating the function of dendritic cells. J. Leukoc. Biol., 2007, Vol. 82, no. 6, pp. 1473-2480.Lin Y-L, Liang Y-C, Chiang B-L. Placental growth factor down-regulates type 1 T helper immune response by modulating the function of dendritic cells. J. Leukoc. Biol., 2007, Vol. 82, no. 6, pp. 1473-2480.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Mor F., Quintana F.J., Cohen I.R. Angiogenesis inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol., 2004, Vol. 172, no. 7, pp. 4618-4623.Ohm J.E., Gabrilovich D.I., Sempowski G.D., Kisseleva E., Parman K.S., Nadaf S., Carbone D.P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood, 2003, Vol. 101, no. 12, pp. 4878-4886.Ohm J.E., Gabrilovich D.I., Sempowski G.D., Kisseleva E., Parman K.S., Nadaf S., Carbone D.P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood, 2003, Vol. 101, no. 12, pp. 4878-4886.Ohm J.E., Gabrilovich D.I., Sempowski G.D., Kisseleva E., Parman K.S., Nadaf S., Carbone D.P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood, 2003, Vol. 101, no. 12, pp. 4878-4886.Ohm J.E., Gabrilovich D.I., Sempowski G.D., Kisseleva E., Parman K.S., Nadaf S., Carbone D.P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood, 2003, Vol. 101, no. 12, pp. 4878-4886.Ohm J.E., Gabrilovich D.I., Sempowski G.D., Kisseleva E., Parman K.S., Nadaf S., Carbone D.P. 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Immunol., 1998, Vol. 160, no. 3, pp. 1224-1232.Oyama T., Ran S., Ishida T., Nadaf S., Kerr L., Carbone D.P., Gabrilovich D.I. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hematopoietic progenitor cells. J. Immunol., 1998, Vol. 160, no. 3, pp. 1224-1232.Oyama T., Ran S., Ishida T., Nadaf S., Kerr L., Carbone D.P., Gabrilovich D.I. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hematopoietic progenitor cells. J. Immunol., 1998, Vol. 160, no. 3, pp. 1224-1232.Oyama T., Ran S., Ishida T., Nadaf S., Kerr L., Carbone D.P., Gabrilovich D.I. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hematopoietic progenitor cells. J. 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The authors declare that there are no conflicts of interest present.