Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI188210.15789/2220-7619-THC-1882REVIEWSОБЗОРЫReview ArticleT helper cell subsets and related target cells in acute COVID-19Т-хелперы и их клетки-мишени при COVID-19KudryavtsevI. V.КудрявцевИгорь Владимирович
Russian Federation

PhD (Biology), Head of the Cell Immunology Laboratory, Department of Immunology, Assistant Professor, Department of Immunology

к.б.н., зав. лабораторией клеточной иммунологии отдела иммунологии, доцент кафедры иммунологии

igorek1981@yandex.ruGolovkinA. S.ГоловкинА. С.
Russian Federation

PhD, MD (Medicine), Head of a Research Group of Genetic Cell Engineering, Institute of Molecular Biology and Genetics

д.м.н., руководитель группы генно-клеточной инженерии Института молекулярной биологии и генетики

golovkin_a@mail.ruTotolianAreg A.ТотолянАрег А.
Russian Federation

RAS Full Member, PhD, MD (Medicine), Professor, Head of the Department of Immunology, Director

академик РАН, д.м.н., профессор, зав. кафедрой иммунологии, директор ФБУН НИИ эпидемиологии и микробиологии имени Пастера

totolian@pasteurorg.ruI.P. Pavlov First St. Petersburg State Medical University of the Ministry of Healthcare of Russian FederationФГБОУ ВО Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова Министерства здравоохранения Российской ФедерацииInstitute of Experimental MedicineФГБНУ Институт экспериментальной медициныV.A. Almazov National Medical Research CentreФГБУ Национальный медицинский исследовательский центр имени В.А. АлмазоваSt. Petersburg Pasteur InstituteФБУН НИИ эпидемиологии и микробиологии имени Пастера12042022040720221234094261502202221022022Copyright ©; 2022, Kudryavtsev I.V., Golovkin A.S., Totolian A.A.Copyright ©; 2022, Кудрявцев И.В., Головкин А.С., Тотолян А.А.2022Kudryavtsev I.V., Golovkin A.S., Totolian A.A.Кудрявцев И.В., Головкин А.С., Тотолян А.А.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/1882

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased “regulatory” Tfh1 cell and increased “pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of “naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

Данный обзор посвящен анализу субпопуляционного состава и фенотипическим изменениям, которые были отмечены для различных субпопуляций Т-хелперов (Th) периферической крови и их клеток-мишеней у пациентов с острой инфекцией, вызванной SARS-CoV-2. Уже в первых работах, посвященных анализу фенотипа и функциональных характеристик дендритных клеток, отмечалось снижение ключевых молекул, отвечающих за презентацию антигенов (HLA-DR), миграцию в лимфоидную ткань (CCR7) и формирование костимуляционного сигнала (CD80 и CD86). Некоторыми исследователями показано, что SARS-CoV-2-специфические Т-хелперы появлялись в циркуляции уже на 2–4 день после появления первых симптомов, а позднее формирование клонов SARS-CoV-2-специфических Th было связано с неблагоприятным исходом COVID-19. В острой фазе инфекции уровень Th1-клеток изменялся слабо, тогда как среди их основных клеток-мишеней — CD8+ Т-лимфоцитов и НК-клеток — в периферической крови преобладали клетки эффекторных популяций с высокой экспрессией маркеров клеточного «старения» (TIM3, PD-1, BTLA, TIGIT и т. д.), а уровень макрофагов жидкости бронхо-альвеолярного лаважа (ЖБАЛ) повышался. При анализе клеток, участвующих в запуске воспаления по 2 типу, большинством исследователей отмечалось увеличение доли CD4+ Т-клеток, обладавших фенотипом и свойствами Th2. Более того, снижение в периферической крови основных клеток-мишеней Th2 — базофилов и эозинофилов — было тесно связано с тяжелым течением COVID-19, тогда как в легочной ткани наблюдалось увеличение уровня тучных клеток и активности медиаторов, высвобождавшихся в ходе их дегрануляции. Содержание Th17 в периферической крови могло быть тесно связано с тяжестью течения COVID-19 — минимальные значения этих клеток были характерны для тяжелых форм заболевания, тогда как в составе ЖБАЛ доля Th17 и концентрации секретируемых ими цитокинов резко возрастала. Увеличение в циркуляции нейтрофилов было тесно связано с тяжесть COVID-19, тогда как в рамках общего пула этих клеток возрастала доля незрелых клеток с пониженной способностью к продукции активных форм кислорода. В большинстве работ отмечалось снижение уровня общего уровня Tfh клеток в циркулирующей крови, тогда как в рамках Tfh увеличивалась доля активированных клеток и отмечалось нарушение баланса между «регуляторными» Tfh1 и «провоспалительными» Th2 и Th17. У пациентов с острым COVID-19 в циркуляции были снижены практически все основные субпопуляции «наивных» В-клеток и В-клеток памяти, но отмечалось увеличение доли эффекторных клеток — циркулирующих предшественников плазматических клеток с фенотипом CD27hiCD38hiCD24–, а также функционально неактивных CD21low В-лимфоцитов. Анализ данных литературы указывает на наличие существенных нарушений в функционировании всех основных субпопуляций Th и их клеток-мишеней в острую фазу COVID-19, которые могут сохраняться после элиминации патогена и являться одной из причин проявления «постковидных» нарушений.

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