Acute infectious mononucleosis (AIM) is a widespread viral disease that mostly affects children. Development of AIM is accompanied by a change in the ratio of immune cells. This is provided by means of different biological processes including the regulation of apoptosis of naive T-cells. One of the potential regulators of apoptosis of T-lymphocytes is a death receptor 3 (DR3). We have studied the role of DR3 in the regulation of apoptosis of naive CD4 + (nTh) and CD8 + (nCTL) T-cells in healthy children and children with AIM. In healthy children as well as in children with AIM, the activation of DR3 is accompanied by inhibition of apoptosis of nTh. In healthy children, the stimulation of DR3 resulted in the increase in apoptosis of nCTL. On the contrary, in children with AIM, the level of apoptosis of nCTL decreased after DR3 activation, which is a positive contribution to the antiviral immune response. In children with AIM, nCTL are characterized by reduced level of apoptosis as compared with healthy children. These results indicate that DR3 can be involved in the reduction of sensitivity of nCTL to apoptosis in children with AIM.
Acute infectious mononucleosis is a widespread viral disease, which most often manifests in childhood. The development of acute infectious mononucleosis is accompanied by the change of the CD4+/CD8+ T-lymphocytes ratio and the increase of the virus-specific CD8+ cytotoxic T-lymphocytes number. One of the T-lymphocytes number regulation mechanisms is the modulation of their progenitor cells apoptosis. The death receptor CD95 takes part in the regulation of T-lymphocytes apoptosis, including naïve T-cells. We studied the effect of CD95 receptor activation on apoptosis of naïve CD4+ and naïve cytotoxic CD8+ T-lymphocytes in healthy children and children with acute infectious mononucleosis. In this study children with acute infectious mononucleosis at the age of 9 to 16 years were included. For comparison healthy children of the same age with no clinical and laboratory signs of the disease were used. Naïve CD4+ and naïve cytotoxic CD8+ T-lymphocytes were isolated by negative magnetic immunoseparation. The analysis of naïve T-cells apoptosis and the CD95 receptor surface expression density was performed by using the flow cytometry analysis. The analysis of T-cells was performed in three variants: freshly isolated naïve CD4+ T-lymphocytes and naïve cytotoxic CD8+ T-lymphocytes, and also cells after 24 hours of the cultivation with anti-CD95 monoclonal antibodies or without them. In healthy children both CD95– and CD95+ naïve CD4+ T-lymphocytes underwent apoptosis. In children with acute infectious mononucleosis CD95– naïve CD4+ T-lymphocytes lost their susceptibility to apoptosis induction. In healthy children and children with acute infectious mononucleosis CD95– naïve cytotoxic CD8+ T-lymphocytes were resistant to apoptosis in contrast to CD95+ naïve CD4+ T-lymphocytes. In healthy children CD95 receptor did not induce apoptosis of isolated naïve CD4+ T-lymphocytes and naïve cytotoxic CD8+ T-lymphocytes. In children with acute infectious mononucleosis CD95 receptor was involved in inhibition of apoptosis of naïve cytotoxic CD8+ T-lymphocytes and did not effect on the level of apoptosis of naïve CD4+ T-lymphocytes. We suggest that CD95-dependent suppression of naïve cytotoxic CD8+ T-lymphocytes apoptosis is a protective mechanism for the maintenance of a sufficient number of cytotoxic T-lymphocytes in the blood for the realization of effective antiviral immune response.
The aim of the investigation was to estimate the relation of CD95 and DR3 receptors activation with apoptosis level of naive cytotoxic Т-lymphocytes (nCТL) in children with acute infectious mononucleosis (AIM).Materials and Methods. The test materials were peripheral blood samples of healthy children and children with AIM. nCTL were isolated by negative immunоmagnetic separation. Specific activation of CD95 and DR3 receptors was performed using monoclonal antibodies. An apoptosis level and expression of receptors were studied by flow cytometry.Results. The percentage of cell apoptosis decreased in children with AIM in freshly isolated nCTL, as well as in CD95 receptor activation compared to healthy children. nCTL apoptosis in healthy children regardless of culture conditions was accompanied by the reduced quantity of CD95 + DR3 -cells and CD95 expression density on their surface. In children with AIM the decrease of these indices required CD95 activation. Compared to healthy children, the percentage of CD95 + DR3 + cells in children with AIM decreased in CD95 activation. In CD95 receptor activation in healthy children and children with AIM, the content of CD95 + DR3 + cells correlated directly with an apoptosis level. DR3 receptor activation was accompanied neither by nCTL apoptosis level change nor the changed content of DR3 + cells in both healthy children and children with AIM.Conclusion. nCTL are less sensitive to apoptosis in children with AIM compared to healthy children. DR3 receptor activation results in no change of nCTL apoptosis level both in healthy children and children with AIM. CD95 activation in patients with AIM is accompanied by increased resistance of CD95 + DR3 -cells to apoptosis and the susceptibility to apoptosis of CD95 + DR3 + cells. The evaluation of nCTL susceptibility to CD95-induced apoptosis in AIM can serve as a subtest to assess the state of a cell component of immune system.
Резюме. При in vitro моделировании инфекционных процессов липополисахарид (ЛПС) применяется как активатор и индуктор апоптоза иммунокомпетентных клеток. На данный момент неясно, является ли ЛПС прямым индуктором апоптоза в Т-клетках человека. Субпопуляции эффекторных и наивных CD4 + Т-хелперов и СD8 + цитотоксических Т-лимфоцитов периферической крови человека были изолированы и культивировались раздельно в присутствии ЛПС. Показано, что ЛПС не является индуктором апоптоза в изученных субпопуляциях Т-клеток.
Резюме. Инфекционный мононуклеоз -широко распространенное заболевание, вызываемое некоторыми представителями семейства Herpesviridae. Острая форма инфекционного мононуклеоза развивается преиму-щественно у детей и на уровне иммунного ответа сопровождается увеличением в периферической крови чис-ла циркулирующих наивных CD4 + и CD8 + Т-лимфоцитов. Нормализация иммунологических показателей до-стигается в течение 4-6 месяцев после выздоровления, что служит индикаторным показателем адекватного функционирования иммунной системы. «Рецепторы смерти» CD95 и DR3 участвуют в инициации апоптоза наивных Т-лимфоцитов, как в норме, так и при остром инфекционном мононуклеозе. Целью работы явилась оценка способности рецепторов CD95 и DR3 инициировать апоптоз наивных CD4 + и CD8 + Т-лимфоцитов у де-тей с инфекционным мононуклеозом в период реконвалесценции. Материалом для исследования послужили образцы периферической крови детей, ранее перенесших инфекционный мононуклеоз. Забор крови прово-дили повторно спустя 4-6 месяцев после заболевания. На момент проведения исследования у детей не выяв-лялись клинические и лабораторные признаки инфекционного мононуклеоза. В качестве группы сравнения выступали дети, которые обследовались нами ранее в период развития у них острого инфекционного монону-клеоза, а также условно здоровые дети. Выделение наивных CD4 + и CD8 + Т-лимфоцитов проводили методом негативной магнитной иммуносепарации. Для специфической стимуляции рецепторов CD95 и DR3 исполь-зовали моноклональные антитела. Уровень апоптоза и экспрессию «рецепторов смерти» оценивали методом проточной цитофлуориметрии. Анализировали свежеизолированные клетки, а также клетки, культивиру-емые с добавлением соответствующих моноклональных антител. Показано, что период выздоровления со-провождался усилением апоптоза свежеизолированных наивных CD4 + и CD8 + Т-лимфоцитов по сравнению с острой фазой инфекционного мононуклеоза. При этом в обеих популяциях наивных Т-лимфоцитов наблю-далось повышение восприимчивости CD95 + клеток к апоптозу. В культуре клеток стимуляция CD95 не при-водила к изменению уровня апоптоза наивных CD4 + и CD8 + Т-лимфоцитов. В свежеизолированных наивных CD4 + и CD8 + Т-лимфоцитах DR3 + клетки были резистентными к апоптозу, а в процессе культивирования их сенситивность изменялась в зависимости от субпопуляционной принадлежности. Так, в культуре наивных CD4 + Т-лимфоцитов DR3 не участвовал в передаче проапоптотического сигнала. В культуре наивных CD8 + Т-лимфоцитов DR3 + клетки усиливали апоптоз клеток, не экспрессирующих этот рецептор. При этом акти-вация DR3 моноклональными антителами в культуре вызывала гибель DR3 + наивных CD8 + Т-лимфоцитов, Адрес для переписки:Филатова Елена Николаевна 603950, Россия, Нижний Новгород, ул. Малая Ямская, 71, Нижегородский НИИЭМ им. акад. И.Н. Блохиной.
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