mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-AOR-2047mimmun-2047Research ArticleОБЗОРЫREVIEWSАнализ регуляторных T-лимфоцитов при грибковых инфекцияхAnalysis of regulatory T lymphocytes in fungal infectionshttps://orcid.org/0000-0002-0567-4616ПоповС. В.PopovS. V.

Попов Сергей Витальевич – доктор медицинских наук, профессор кафедры общей врачебной практики, врач-уролог, Медицинский институт

Москва

Popov Sergey V., PhD, MD (Medicine), Professor, Department of General Practice, Clinical Urologist, Medical Institute

Moscow

servit77@yandex.ruhttps://orcid.org/0000-0002-7373-7156ШмельковИлья ЮрьевичShmelkovI. Yu.

Шмельков Илья Юрьевич – врач-уролог, соискатель кафедры общей врачебной практики Медицинского института

Москва

Shmelkov Ilya Yu., Clinical Urologist, PhD Applicant, Department of General Practice, Medical Institute

Moscow

doctorshmelkov@gmail.comhttps://orcid.org/0000-0003-1600-5335ХайдуковС. В.KhaidukovS. V.

Хайдуков Сергей Валерьевич ФГБУН «Институт биоорганической химии имени академиков М.М. Шемякина и Ю.А. Овчинникова» Российской академии наук

117997, Москва, ГСП-7, ул. Миклухо-Маклая, 16/10

Khaidukov Sergey V., PhD, MD (Biology), Senior Research Associate

117197, Moscow, GSP-7, Miklukho-Maklay str., 16/10

khsergey54@mail.ruФГАОУ ВО «Российский университет дружбы народов»РоссияPeoples' friendship university of RussiaRussian FederationФГБУН «Институт биоорганической химии имени академиков М.М. Шемякина и Ю.А. Овчинникова» Российской академии наукРоссияM. Shemyakin and Yu. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesRussian Federation20203112202022610551064Copyright © Попов С.В., Шмельков И.Ю., Хайдуков С.В., 20212021Попов С.В., Шмельков И.Ю., Хайдуков С.В.Popov S.V., Shmelkov I.Y., Khaidukov S.V.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/2047

Показатели заболеваемости и смертности при инвазивных микозах предопределяют необходимость совершенствования методов их своевременной диагностики с оценкой иммунного статуса пациентов. Оценка иммунного статуса пациента позволяет клиницисту прогнозировать развитие и течение грибковых инфекций. В то же время выявление условно-патогенного микоза у пациента без иммунодефицита должно определять необходимость поиска скрытого иммунного дефекта. Определение причины таких иммунодефицитов может способствовать выработке эффективной стратегии как этиотропной, так и иммунной терапии пациентов с инвазивными микозами. В настоящее время функции регуляторных Т-лимфоцитов, поддерживающих иммунологическую толерантность, при грибковой инфекции продолжают оставаться не полностью изученными. В представленном обзоре продемонстрированы данные исследований на экспериментальных моделях, свидетельствующие о том, что регуляторные Т-лимфоциты способны подавлять иммунные ответы на грибки посредством стимулирования иммуносупрессивной среды. Определено, что регуляторные Т-лимфоциты используют Toll-like рецептор 2 для достижения иммуносупрессии при кандидозных инфекциях. Баланс количества и функции регуляторных Т-лимфоцитов имеет существенное значение для элиминации грибковых патогенов и защиты от постинфекционных иммунопатологических состояний. Установлено, что регуляторные Т-лимфоциты обеспечивают защиту на ранней стадии кандидозной инфекции, когда в результате подавления интерлейкина 2 (IL-2) они усиливают дифференцировку T-хелперов 17 (Th17) и клиренс грибка. При этом на более поздних стадиях инфекции регуляторные Т-лимфоциты оказывают ингибирующий эффект. Баланс между Th17 и регуляторными Т-лимфоцитами в слизистой оболочке признан основным фактором для разграничения комменсального носительства и инфекции Candida albicans. Представлены результаты исследования, свидетельствующие о том, что при диссеминированном кандидозе экспансия регуляторных Т-лимфоцитов стимулирует Th17- клеточный ответ, управляющий течением заболевания. Механизмы, контролирующие гомеостаз регуляторных Т-лимфоцитов, являются основными для обеспечения эффективной защиты от патогенов, а также для контроля иммунопатологических состояний, связанных с кандидозной инфекцией. В обзоре представлены данные, позволившие установить роль трансформирующего фактора роста бета 1 (TGF-β1) в повышении жизнеспособности регуляторных Т-лимфоцитов, что соотносится с выраженной иммуномодулирующей ролью этих клеток во время более поздней фазы кандидозных инфекций слизистой оболочки. Продемонстрированы также данные о том, что во время криптококковой инфекции индуцируются легочные регуляторные Т-лимфоциты, которые преимущественно подавляют T-хелперы второго типа (Th2), поддерживая тем самым ее течение. Экспансия регуляторных Т-лимфоцитов при введении комплекса интерлейкина 2/ антител к интерлейкину 2 (IL-2/антиIL-2) во время криптококковой инфекции приводила к снижению выработки иммуноглобулина E (IgE) и уменьшению аллергического воспаления дыхательных путей. Необходимо отметить, что уточнение прогностического значения регуляторных Т-лимфоцитов при грибковой инфекции у человека может стать основой для разработки основных принципов адресной иммунотерапии.

Morbidity and mortality rates in invasive mycoses determine the need to improve methods for their timely diagnosis by assessment the patients’ immune status. Evaluation of individual immune status allows the clinician to predict the development and course of fungal infections. At the same time, identification of opportunistic mycosis in immunocompetent patients should require a search for some hidden immune deficiency. Determining the cause of such immune defects can help develop an effective strategy for both etiotropic and immune therapy of patients with invasive mycoses. Currently, the functions of regulatory T lymphocytes that support immunological tolerance in fungal infections remain to be incompletely studied. In this review, we present experimental works which suggest that the regulatory T lymphocytes are able to suppress immune responses to fungi by stimulating the immunosuppressive environment. It was shown that regulatory T lymphocytes use Toll-like receptor 2 to achieve immunosuppression in Candida infections. The balance between the number and function of regulatory T lymphocytes is essential for elimination of fungal pathogens and protection against post-infectious immunopathological conditions. It was found that the regulatory T lymphocytes provide protection at an early stage of Candida infection, since, due to IL-2 suppression, they enhance Th17 differentiation and clearance of fungi. Moreover, at the later stages of infection, the regulatory T lymphocytes have an inhibitory effect. The balance between Th17 and regulatory T lymphocytes in mucosal lining is considered the main factor for distinguishing between commensal carriage and Candida albicans infection. The study is presented which indicate that disseminated candidiasis associated with expansion of regulatory T lymphocytes stimulates a Th17-cell response that controls the course of the disease. The mechanisms that control regulatory T lymphocytes homeostasis are essential for providing effective protection against pathogens, as well as for controlling the immunopathological conditions associated with Candida infection. The review presents data that have established the role of TGF-β1 in increasing the viability of regulatory T lymphocytes, which is correlated with the pronounced immunomodulating role of these cells at the later phase of Candida infections of the mucous membrane. It has been also demonstrated that the pulmonary regulatory Tlymphocytes are induced during cryptococcal infection, which predominantly suppresses Th2 cells, thereby supporting its course. Expansion of the regulatory T lymphocytes upon administration of IL-2/antiIL-2 complex during cryptococcal infection led to a decrease in IgE production and a decrease in allergic airway inflammation. It should be noted that refinement of prognostic value of the regulatory T lymphocytes in human fungal infections may substantiate the basic principles of targeted immunotherapy.

регуляторные Т-лимфоцитыцитотоксический Т-лимфоцитарный антиген 4 (CTLA-4)Th17интерлейкиныToll-like рецептор (TLR)грибковые инфекциикандидозTregFoxP3CTLA-4Th17interleukinsToll-like receptors (TLR)fungal infectionscandidiasisReferencesКлимко Н.Н. Микотический сепсис. Сепсис: избранные вопросы диагностики и лечения. Практическое руководство / Под ред. Н.В. Дмитриевой, И.Н. Петуховой, Е.Г. Громовой. М.: АБВ-пресс, 2018. С. 371-388.Klimko N.N. Mycotic sepsis. Sepsis: selected issues of diagnosis and treatment. A practical guide. Ed. N.V. Dmitrieva, I.N. Petukhova, E.G. Gromova]. Moscow: ABV-Press, 2018. pp. 371-388. (In Russ.)Хайдуков С.В., Зурочка А.В. Цитометрический анализ субпопуляций Т-хелперов (Th1, Th2, Treg, Th17, Т-хелперы активированные) // Медицинская иммунология, 2011. Т. 13, № 1. С. 7-16. doi: 10.15789/1563-0625-2011-1-7-16Khaidukov S.V., Zurochka A.V. Analysis of t helper subpopulations (Th1, Th2, Treg, Th17, activated T-helpers) by means of flow cytometry. Meditsinskaya immunologiya = Medical Immunology (Russia), 2011, Vol. 13, no. 1, pp. 7-16. (In Russ.) doi: 10.15789/1563-0625-2011-1-7-16.Хайдуков С.В., Зурочка А.В., Тотолян Арег А., Черешнев В.А. Основные и малые популяции лимфоцитов периферической крови человека и их нормативные значения (методом многоцветного цитометрического анализа) // Медицинская иммунология, 2009. T. 11, № 2-3. C. 227-238. doi: 10.15789/1563-0625-2009-2-3-227-238.Khaidukov S.V., Zurochka A.V., Totolian Areg A., Chereshnev V.A. Major and lymphocyte populations of human peripheral blood lymphocytes and their reference values, as assayed by multi-colour cytometry. Meditsinskaya immunologiya = Medical Immunology (Russia), 2009, Vol. 11, no. 2-3, pp. 227-238. (In Russ). doi: 10.15789/1563-0625-2009-2-3-227-238.Agostini M., Cenci E., Pericolini E., Nocentini G., Bistoni G., Vecchiarelli A., Riccardi C. The glucocorticoidinduced tumor necrosis factor receptor-related gene modulates the response to Candida albicans infection. Infect. Immun., 2005, Vol. 73, no. 11, pp. 7502-7508.Agostini M., Cenci E., Pericolini E., Nocentini G., Bistoni G., Vecchiarelli A., Riccardi C. The glucocorticoidinduced tumor necrosis factor receptor-related gene modulates the response to Candida albicans infection. Infect. Immun., 2005, Vol. 73, no. 11, pp. 7502-7508.Akira S., Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett., 2003, Vol. 85, pp. 85-95.Akira S., Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett., 2003, Vol. 85, pp. 85-95.Armstrong-James D., Meintjes G., Brown G.D. A neglected epidemic: fungal infections in HIV/AIDS. Trends Microbiol., 2014, vol. 22, no. 3, pp. 120-127.Armstrong-James D., Meintjes G., Brown G.D. A neglected epidemic: fungal infections in HIV/AIDS. Trends Microbiol., 2014, vol. 22, no. 3, pp. 120-127.Belkaid Y., Piccirillo C.A., Mendez S., Shevach E.M., Sacks D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature, 2002, Vol. 420, no. 6915, pp. 502-507.Belkaid Y., Piccirillo C.A., Mendez S., Shevach E.M., Sacks D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature, 2002, Vol. 420, no. 6915, pp. 502-507.Belkaid Y., Rouse B.T. Natural regulatory T cells in infectious disease. Nat. Immunol., 2005, Vol. 6, no. 4, pp. 353-360.Belkaid Y., Rouse B.T. Natural regulatory T cells in infectious disease. Nat. Immunol., 2005, Vol. 6, no. 4, pp. 353-360.Bhaskaran N., Quigley C., Weinberg A., Huang A., Popkin D., Pandiyan P. Transforming growth factor-β1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection. Mucosal Immunol., 2016, Vol. 9, no. 4, pp. 1015-1026.Bhaskaran N., Quigley C., Weinberg A., Huang A., Popkin D., Pandiyan P. Transforming growth factor-β1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection. Mucosal Immunol., 2016, Vol. 9, no. 4, pp. 1015-1026.Blackstock R., Murphy J.W. Role of interleukin-4 in resistance to Cryptococcus neoformans infection. Am. J. Respir. Cell Mol. Biol., 2004, vol. 30, no. 1, pp. 109-117.Blackstock R., Murphy J.W. Role of interleukin-4 in resistance to Cryptococcus neoformans infection. Am. J. Respir. Cell Mol. Biol., 2004, vol. 30, no. 1, pp. 109-117.Bongomin F., Gago S., Oladele R.O., Denning D.W. Global and multi-national prevalence of fungal diseasesestimate precision. J. Fungi (Basel), 2017, vol. 3, no.4. pii: E57. doi: 10.3390/jof3040057.Bongomin F., Gago S., Oladele R.O., Denning D.W. Global and multi-national prevalence of fungal diseasesestimate precision. J. Fungi (Basel), 2017, vol. 3, no.4. pii: E57. doi: 10.3390/jof3040057.Bonifazi P., Zelante T., d’Angelo C., de Luca A., Moretti S., Bozza S., Perruccio K., Iannitti R.G., Giovannini G., Volpi C., Fallarino F., Puccetti P., Romani L. Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans. Mucosal Immunol., 2009, Vol. 2, no. 4, pp. 362-374.Bonifazi P., Zelante T., d’Angelo C., de Luca A., Moretti S., Bozza S., Perruccio K., Iannitti R.G., Giovannini G., Volpi C., Fallarino F., Puccetti P., Romani L. Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans. Mucosal Immunol., 2009, Vol. 2, no. 4, pp. 362-374.Bours M.J., Swennen E.L.R., Di Virgilio F., Cronstein B.N., Dagnelie P.C. Adenosine 5’-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther., 2006, Vol. 112, no. 2, pp. 358-404.Bours M.J., Swennen E.L.R., Di Virgilio F., Cronstein B.N., Dagnelie P.C. Adenosine 5’-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther., 2006, Vol. 112, no. 2, pp. 358-404.Brown G.D., Denning D.W., Gow N.A., Levitz S.M., Netea M.G., White T.C. Hidden killers: human fungal infections. Sci. Transl. Med., 2012, Vol. 4, no. 165, 165rv13. doi: 10.1126/scitranslmed.3004404.Brown G.D., Denning D.W., Gow N.A., Levitz S.M., Netea M.G., White T.C. Hidden killers: human fungal infections. Sci. Transl. Med., 2012, Vol. 4, no. 165, 165rv13. doi: 10.1126/scitranslmed.3004404.Chang C.C., Levitz S.M. Fungal immunology in clinical practice: magical realism or practical reality? Med. Mycol., 2019, Vol. 57, pp. S294-S306.Chang C.C., Levitz S.M. Fungal immunology in clinical practice: magical realism or practical reality? Med. Mycol., 2019, Vol. 57, pp. S294-S306.Coelho C., Tesfa L., Zhang J., Rivera J., Goncalves T., Casadevall A. Analysis of cell cycle and replication of mouse macrophages after in vivo and in vitro Cryptococcus neoformans infection using laser scanning cytometry. Infect. Immun., 2012, Vol. 80, no. 4, pp. 1467-1478.Coelho C., Tesfa L., Zhang J., Rivera J., Goncalves T., Casadevall A. Analysis of cell cycle and replication of mouse macrophages after in vivo and in vitro Cryptococcus neoformans infection using laser scanning cytometry. Infect. Immun., 2012, Vol. 80, no. 4, pp. 1467-1478.Collison L.W., Workman C.J., Kuo T.T., Boyd K., Wang Y., Vignali K.M., Cross R., Sehy D., Blumberg R.S., Vignali D.A.A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 2007, Vol. 450, no. 7169, pp. 566-569.Collison L.W., Workman C.J., Kuo T.T., Boyd K., Wang Y., Vignali K.M., Cross R., Sehy D., Blumberg R.S., Vignali D.A.A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 2007, Vol. 450, no. 7169, pp. 566-569.Conti H.R., Shen F., Nayyar N., Stocum E., Sun J.N., Lindemann M.J., Ho A.W., Hai J.H., Yu J.J., Jung J.W., Filler S.G., Masso-Welch P., Edgerton M., Gaffen S.L. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med., 2009, Vol. 206, no. 2, pp. 299-311.Conti H.R., Shen F., Nayyar N., Stocum E., Sun J.N., Lindemann M.J., Ho A.W., Hai J.H., Yu J.J., Jung J.W., Filler S.G., Masso-Welch P., Edgerton M., Gaffen S.L. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med., 2009, Vol. 206, no. 2, pp. 299-311.Delsing C.E., Gresnigt M.S., Leentjens J., Preijers F., Frager F.A., Kox M., Monneret G., Venet F., BleekerRovers C.P., van de Veerdonk F.L., Pickkers P., Pachot A., Kullberg B.J., Netea M.G. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect. Dis., 2014, Vol. 14, 166. doi: 10.1186/1471-2334-14-166.Delsing C.E., Gresnigt M.S., Leentjens J., Preijers F., Frager F.A., Kox M., Monneret G., Venet F., BleekerRovers C.P., van de Veerdonk F.L., Pickkers P., Pachot A., Kullberg B.J., Netea M.G. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect. Dis., 2014, Vol. 14, 166. doi: 10.1186/1471-2334-14-166.Fontenot J.D., Gavin M.A., Rudensky A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol., 2003, Vol. 4, no. 4, pp. 330-336.Fontenot J.D., Gavin M.A., Rudensky A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol., 2003, Vol. 4, no. 4, pp. 330-336.Fulton R.B., Meyerholz D.K., Varga S.M. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J. Immunol., 2010, Vol. 185, no. 4, pp. 2382-2392.Fulton R.B., Meyerholz D.K., Varga S.M. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J. Immunol., 2010, Vol. 185, no. 4, pp. 2382-2392.Giovannetti A., Pierdominici M., di Iorio A., Cianci R., Murdaca G., Puppo F., Pandolfi F., Paganelli R. Apoptosis in the homeostasis of the immune system and in human immune mediated diseases. Curr. Pharm. Des., 2008, Vol. 14, no. 3, pp. 253-268.Giovannetti A., Pierdominici M., di Iorio A., Cianci R., Murdaca G., Puppo F., Pandolfi F., Paganelli R. Apoptosis in the homeostasis of the immune system and in human immune mediated diseases. Curr. Pharm. Des., 2008, Vol. 14, no. 3, pp. 253-268.Grahnert A., Richter T., Piehler D., Eschke M., Schulze B., Müller U., Protschka M., Köhler G., Sabat R., Brombacher F., Alber G. IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection. PLoS ONE, 2014, Vol. 9, no. 1, e87341. doi: 10.1371/journal.pone.0087341.Grahnert A., Richter T., Piehler D., Eschke M., Schulze B., Müller U., Protschka M., Köhler G., Sabat R., Brombacher F., Alber G. IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection. PLoS ONE, 2014, Vol. 9, no. 1, e87341. doi: 10.1371/journal.pone.0087341.Haeryfar S.M., DiPaolo R.J., Tscharke D.C., Bennink J.R., Yewdell J.W. Regulatory T cells suppress CD8+ T cell responses induced by direct priming and cross-priming and moderate immunodominance disparities. J. Immunol., 2005, Vol. 174, no. 6, pp. 3344-3351.Haeryfar S.M., DiPaolo R.J., Tscharke D.C., Bennink J.R., Yewdell J.W. Regulatory T cells suppress CD8+ T cell responses induced by direct priming and cross-priming and moderate immunodominance disparities. J. Immunol., 2005, Vol. 174, no. 6, pp. 3344-3351.Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, Vol. 299, no. 5609, pp. 1057-1061.Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, Vol. 299, no. 5609, pp. 1057-1061.Kechichian T.B., Shea J., del Poeta M. Depletion of alveolar macrophages decreases the dissemination of a glucosylceramidedeficient mutant of Cryptococcus neoformans in immunodeficient mice. Infect. Immun., 2007, Vol. 75, no. 10, pp. 4792-4798.Kechichian T.B., Shea J., del Poeta M. Depletion of alveolar macrophages decreases the dissemination of a glucosylceramidedeficient mutant of Cryptococcus neoformans in immunodeficient mice. Infect. Immun., 2007, Vol. 75, no. 10, pp. 4792-4798.Koguchi Y., Kawakami K. Cryptococcal infection and Th1-Th2 cytokine balance. Int. Rev. Immunol., 2002, Vol. 21, no. 4-5, pp. 423-438.Koguchi Y., Kawakami K. Cryptococcal infection and Th1-Th2 cytokine balance. Int. Rev. Immunol., 2002, Vol. 21, no. 4-5, pp. 423-438.Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 cells. Annu. Rev. Immunol., 2009, Vol. 27, pp. 485-517.Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 cells. Annu. Rev. Immunol., 2009, Vol. 27, pp. 485-517.Kostareva O.S., Gabdulkhakov A.G., Kolyadenko I.A., Garber M.B., Tishchenko S.V. Interleukin-17: functional and structural features, application as a therapeutic target. Biochemistry (Mosc.), 2019, Vol. 84, no. 1, pp. 193-205.Kostareva O.S., Gabdulkhakov A.G., Kolyadenko I.A., Garber M.B., Tishchenko S.V. Interleukin-17: functional and structural features, application as a therapeutic target. Biochemistry (Mosc.), 2019, Vol. 84, no. 1, pp. 193-205.Lin W., Truong N., Grossman W.J., Haribhai D., Williams C.B., Wang J., Martín M.G., Chatila T.A. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J. Allergy Clin. Immunol., 2005, vol. 116, no. 5, pp. 1106-1115.Lin W., Truong N., Grossman W.J., Haribhai D., Williams C.B., Wang J., Martín M.G., Chatila T.A. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J. Allergy Clin. Immunol., 2005, vol. 116, no. 5, pp. 1106-1115.Loebbermann J., Thornton H., Durant L., Sparwasser T., Webster K.E., Sprent J., Culley F.J., Johansson C., Openshaw P.J. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol., 2012, Vol. 5, no. 2, pp. 161-172.Loebbermann J., Thornton H., Durant L., Sparwasser T., Webster K.E., Sprent J., Culley F.J., Johansson C., Openshaw P.J. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol., 2012, Vol. 5, no. 2, pp. 161-172.Mills K.H. Regulatory T cells: friend or foe in immunity to infection? Nat. Rev. Immunol., 2004, Vol. 4, no. 11, pp. 841-855.Mills K.H. Regulatory T cells: friend or foe in immunity to infection? Nat. Rev. Immunol., 2004, Vol. 4, no. 11, pp. 841-855.Müller U., Stenzel W., Köhler G., Werner C., Polte T., Hansen G., Schütze N., Straubinger R.K., Blessing M., McKenzie A.N., Brombacher F., Alber G. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J. Immunol., 2007, Vol. 179, no. 8, pp. 5367-5377.Müller U., Stenzel W., Köhler G., Werner C., Polte T., Hansen G., Schütze N., Straubinger R.K., Blessing M., McKenzie A.N., Brombacher F., Alber G. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J. Immunol., 2007, Vol. 179, no. 8, pp. 5367-5377.Murdock B.J., Huffnagle G.B., Olszewski M.A., Osterholzer J.J. Interleukin-17A enhances host defense against cryptococcal lung infection through effects mediated by leukocyte recruitment, activation, and gamma interferon production. Infect. Immun., 2014, Vol. 82, no. 3, pp. 937-948.Murdock B.J., Huffnagle G.B., Olszewski M.A., Osterholzer J.J. Interleukin-17A enhances host defense against cryptococcal lung infection through effects mediated by leukocyte recruitment, activation, and gamma interferon production. Infect. Immun., 2014, Vol. 82, no. 3, pp. 937-948.Netea M.G., Sutmuller R., Hermann C., Van der Graaf C.A., Van der Meer J.W., van Krieken J.H., Hartung T., Adema G., Kullberg B.J. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol., 2004, Vol. 172, no. 6, pp. 3712-3718.Netea M.G., Sutmuller R., Hermann C., Van der Graaf C.A., Van der Meer J.W., van Krieken J.H., Hartung T., Adema G., Kullberg B.J. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol., 2004, Vol. 172, no. 6, pp. 3712-3718.Netea M.G., van Der Graaf C.A., Vonk A.G., Verschueren I., van Der Meer J.W., Kullberg B.J. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis., 2002, Vol. 185, no. 10, pp. 1483-1489.Netea M.G., van Der Graaf C.A., Vonk A.G., Verschueren I., van Der Meer J.W., Kullberg B.J. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis., 2002, Vol. 185, no. 10, pp. 1483-1489.Niedbala W., Wei X.-Q., Cai B., Hueber A.J., Leung B.P., McInnes I.B., Liew F.Y. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur. J. Immunol., 2007, Vol. 37, no. 11, pp. 3021-3029.Niedbala W., Wei X.-Q., Cai B., Hueber A.J., Leung B.P., McInnes I.B., Liew F.Y. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur. J. Immunol., 2007, Vol. 37, no. 11, pp. 3021-3029.Pandiyan P., Conti H.R., Zheng L., Peterson A.C., Mathern D.R., Hernández-Santos N., Edgerton M., Gaffen S.L., Lenardo M.J. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity, 2011, Vol. 34, no. 3, pp. 422-434.Pandiyan P., Conti H.R., Zheng L., Peterson A.C., Mathern D.R., Hernández-Santos N., Edgerton M., Gaffen S.L., Lenardo M.J. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity, 2011, Vol. 34, no. 3, pp. 422-434.Pandiyan P., Zheng L., Ishihara S., Reed J., Lenardo M.J. CD4+CD25+FoxP3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature. Immunology, 2007, Vol. 8, no. 12, pp. 1353-1362.Pandiyan P., Zheng L., Ishihara S., Reed J., Lenardo M.J. CD4+CD25+FoxP3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature. Immunology, 2007, Vol. 8, no. 12, pp. 1353-1362.Park B.J., Wannemuehler K.A., Marston B.J., Govender N., Pappas P.G., Chiller T.M. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS, 2009, Vol. 23, no. 4, pp. 525-530.Park B.J., Wannemuehler K.A., Marston B.J., Govender N., Pappas P.G., Chiller T.M. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS, 2009, Vol. 23, no. 4, pp. 525-530.Read S., Malmstrom V., Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med., 2000, Vol. 192, no. 2, pp. 295-302.Read S., Malmstrom V., Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med., 2000, Vol. 192, no. 2, pp. 295-302.Romani L. Immunity to fungal infections. Nat. Rev. Immunol., 2011, Vol. 11, no. 4, pp. 275-288.Romani L. Immunity to fungal infections. Nat. Rev. Immunol., 2011, Vol. 11, no. 4, pp. 275-288.Ruckwardt T.J., Bonaparte K.L., Nason M.C., Graham B.S. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. J. Virol., 2009, Vol. 83, no. 7, pp. 3019-3028.Ruckwardt T.J., Bonaparte K.L., Nason M.C., Graham B.S. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. J. Virol., 2009, Vol. 83, no. 7, pp. 3019-3028.Schmitz I., Schneider C., Fröhlich A., Frebel H., Christ D., Leonard W.J., Sparwasser T., Oxenius A., Freigang S., Kopf M. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS Pathog., 2013, Vol. 9, no. 5, e1003362. doi: 10.1371/journal.ppat.1003362.Schmitz I., Schneider C., Fröhlich A., Frebel H., Christ D., Leonard W.J., Sparwasser T., Oxenius A., Freigang S., Kopf M. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS Pathog., 2013, Vol. 9, no. 5, e1003362. doi: 10.1371/journal.ppat.1003362.Schubert L.A., Jeffery E., Zhang Y., Ramsdell F., Ziegler S.F. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem., 2001, Vol. 276, no. 40, pp. 37672-37679.Schubert L.A., Jeffery E., Zhang Y., Ramsdell F., Ziegler S.F. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem., 2001, Vol. 276, no. 40, pp. 37672-37679.Schulze B., Piehler D., Eschke M., von Buttlar H., Köhler G., Sparwasser T., Alber G. CD4(+) FoxP3(+) regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection. Eur. J. Immunol., 2014, Vol. 44, no. 12, pp. 3596-3604.Schulze B., Piehler D., Eschke M., von Buttlar H., Köhler G., Sparwasser T., Alber G. CD4(+) FoxP3(+) regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection. Eur. J. Immunol., 2014, Vol. 44, no. 12, pp. 3596-3604.Shevach E.M. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol., 2002, Vol. 2, no. 6, pp. 389-400.Shevach E.M. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol., 2002, Vol. 2, no. 6, pp. 389-400.Shevach E.M. Immunology: regulating suppression. Science, 2008, Vol. 322, no. 5899, pp. 202-203.Shevach E.M. Immunology: regulating suppression. Science, 2008, Vol. 322, no. 5899, pp. 202-203.Shevach E.M. Mechanisms of FoxP3+ T regulatory cell-mediated suppression. Immunity, 2009, Vol. 30, no. 5, pp. 636-645.Shevach E.M. Mechanisms of FoxP3+ T regulatory cell-mediated suppression. Immunity, 2009, Vol. 30, no. 5, pp. 636-645.Shoham S., Levitz S.M. The immune response to fungal infections. Br. J. Haematol., 2005, Vol. 129, no. 5, pp. 569-582.Shoham S., Levitz S.M. The immune response to fungal infections. Br. J. Haematol., 2005, Vol. 129, no. 5, pp. 569-582.Stephen-Victor E., Bosschem I., Haesebrouck F., Bayry J. The Yin and Yang of regulatory T cells in infectious diseases and avenues to target them. Cell. Microbiol., 2017, Vol.19, no. 6. pp. 1-9.Stephen-Victor E., Bosschem I., Haesebrouck F., Bayry J. The Yin and Yang of regulatory T cells in infectious diseases and avenues to target them. Cell. Microbiol., 2017, Vol.19, no. 6. pp. 1-9.Sutmuller R.P., den Brok M.H., Kramer M., Bennink E.J., Toonen L.W., Kullberg B.J., Joosten L.A., Akira S., Netea M.G., Adema G.J. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest., 2006, Vol. 116, no. 2, pp. 485-494.Sutmuller R.P., den Brok M.H., Kramer M., Bennink E.J., Toonen L.W., Kullberg B.J., Joosten L.A., Akira S., Netea M.G., Adema G.J. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest., 2006, Vol. 116, no. 2, pp. 485-494.Szymczak W.A., Sellers R.S., Pirofski L.A. IL-23 dampens the allergic response to Cryptococcus neoformans through IL-17-independent and -dependent mechanisms. Am. J. Pathol., 2012, Vol. 180, no. 4, pp. 1547-1559.Szymczak W.A., Sellers R.S., Pirofski L.A. IL-23 dampens the allergic response to Cryptococcus neoformans through IL-17-independent and -dependent mechanisms. Am. J. Pathol., 2012, Vol. 180, no. 4, pp. 1547-1559.Underhill D.M., Ozinsky A., Hajjar A.M., Stevens A., Wilson C.B., Bassetti M., Aderem A. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature, 1999, Vol. 401, no. 6755, pp. 811-815.Underhill D.M., Ozinsky A., Hajjar A.M., Stevens A., Wilson C.B., Bassetti M., Aderem A. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature, 1999, Vol. 401, no. 6755, pp. 811-815.van Hamburg J.P., de Bruijn M.J., de Almeida C.R., van Zwam M., van Meurs M., de Haas E., Boon L., Samsom J.N., Hendriks R.W. Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but constrains Th17-mediated pathology. Eur. J. Immunol., 2008, Vol. 38, pp. 2573-2586.van Hamburg J.P., de Bruijn M.J., de Almeida C.R., van Zwam M., van Meurs M., de Haas E., Boon L., Samsom J.N., Hendriks R.W. Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but constrains Th17-mediated pathology. Eur. J. Immunol., 2008, Vol. 38, pp. 2573-2586.von Boehmer H., Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat. Rev. Drug Discov., 2013, Vol. 12, no. 1, pp. 51-63.von Boehmer H., Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat. Rev. Drug Discov., 2013, Vol. 12, no. 1, pp. 51-63.Whibley N., Gaffen S.L. Brothers in arms: Th17 and Treg responses in Candida albicans immunity. PLoS Pathog., 2014, Vol. 10, no. 12, e1004456. doi: 10.1371/journal.ppat.1004456.Whibley N., Gaffen S.L. Brothers in arms: Th17 and Treg responses in Candida albicans immunity. PLoS Pathog., 2014, Vol. 10, no. 12, e1004456. doi: 10.1371/journal.ppat.1004456.Whibley N., MacCallum D.M., Vickers M.A., Zafreen S., Waldmann H., Hori S., Gaffen S.L., Gow N.A.R., Barker R.N., Hall A.M. Expansion of Foxp3+ T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge. Eur. J. Immunol., 2014, Vol. 44, pp. 1069-1083.Whibley N., MacCallum D.M., Vickers M.A., Zafreen S., Waldmann H., Hori S., Gaffen S.L., Gow N.A.R., Barker R.N., Hall A.M. Expansion of Foxp3+ T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge. Eur. J. Immunol., 2014, Vol. 44, pp. 1069-1083.Wildin R.S., Smyk-Pearson S., Filipovich A.H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet., 2002, Vol. 39, no. 8, pp. 537-545.Wildin R.S., Smyk-Pearson S., Filipovich A.H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet., 2002, Vol. 39, no. 8, pp. 537-545.Wing J.B., Sakaguchi S. Foxp3(+) T(reg) cells in humoral immunity. Int. Immunol., 2014, Vol. 26, no. 2, pp. 61-69.Wing J.B., Sakaguchi S. Foxp3(+) T(reg) cells in humoral immunity. Int. Immunol., 2014, Vol. 26, no. 2, pp. 61-69.Wing K., Onishi Y., Prieto-Martin P., Yamaguchi T., Miyara M., Fehervari Z., Nomura T., Sakaguchi S. CTLA-4 control over FoxP3+ regulatory T cell function. Science, 2008, Vol. 322, no. 5899, pp. 271-275.Wing K., Onishi Y., Prieto-Martin P., Yamaguchi T., Miyara M., Fehervari Z., Nomura T., Sakaguchi S. CTLA-4 control over FoxP3+ regulatory T cell function. Science, 2008, Vol. 322, no. 5899, pp. 271-275.

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