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Особенности активации Тлимфоцитов при тяжелом ковиде

Интересная статья (препринт) о механизме воспалительного ответа и лимфопении (лимфоцитопении) с вовлечением Т-хелперов при тяжелом ковиде.
В присутствии шипикового белка S1 и индуцированного им повышенного количества фактора некроза опухоли альфа, иммунодоминирующие Т лимфоциты (те, которые реугируют на этот белок вируса) теряют часть своих функций, не могут размножаться, но проявляют высокую чувствительность к цитокинам, заспускаюащим клеточную смерть (особенно к ФНО), изза аутокринного эффекта, направленного на эффекторную функцию, но в итоге гибнут - апоптоз, в частности, индуцированная активацией клеточная смерть..
Белок коронавируса каким-то образом угнетает активность регуляторной части генов лимфоцита, но гиперактивирует участки, работа которых приводит к выработке воспалительных цитокинов и рецепторов.
Если блокировать ФНО, таким образом можно защитить эту популяцию клеток от гибели, и они смогут и сохраниться, восстановить свою способность к пролиферации и помочь выздоравливать. In vitro и антитела к ФНО, и к его рецептору Fas показали хорошую защитную активность.
Это явление самоактивации и гибели Т лимфоцитов отмечается только у тех, у кого тяжелая форма ковида. Потому что у них в легких есть популяция резидентных Т-лимфоцитов памяти, реагриующих на S1 белок именно таким образом. Это показали исследования тканей легких пациентов, которым понадобилась пересадка легких после ковида.. Так что для некоторых S1 белок коронавируса играет роль, как бы, суперантигена (не совсем по механизму, но несколько похоже по результату).
Вопрос, откуда в легких тяжелых ковидных взялись Т клетки памяти, чувствительные к S1 белку коронавируса, и  почему только у них такая особенность, в статье не рассматривался
In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.
Herein, we show that severe COVID-19-associated lymphopenia is a predominant CD4+lymphopenia and associated with an increased risk for mortality. Overall, severe COVID-19 disease was associated with a significant diminution in the peripheral CD4+/CD8+ratios, whereas recovered,mild COVID-19, patients demonstrated a preservation of normalCD4+/CD8+ratios.Based on thesefindings, we assessed the function of peripheral CD4+T cells from severe COVID-19 versus mildrecoveredCOVID-19patients to evaluate immune mechanisms driving CD4+lymphopenia. Indeed, we found that a disproportionate increase in TNF-production and cytotoxic function from CD4+T cells, but not CD8+T cells, in response to the immunodominant antigen, S1, was evident in severe COVID-19 disease. Wealsofound that S1-specific autocrineTNF--dependent production from CD4+T cells themselves, and enhanced TNF-responsiveness via TNFRI are key mechanisms leading to impaired CD4+proliferation and activation induced cell death (AICD)and contribute to CD4+lymphopenia. Together, our findings point to a skewed pro-inflammatory CD4+T cell response among severe COVID-19 patients that is central to CD4+T cell dysfunction and that plausibly contributes to the immunopathogenesis of severe disease.While our studies found that S1 is the immunodominant antigen for SARS-CoV-2-induced T cell responses, we also detected significant effector T cell responses to other viral antigens, namely S2, NCAP and VEMP. However, CD4+T cell responses to these antigens fromsevere diseasepatients did not demonstrate a hierarchical dominance of TNF-to these antigens as the S1 response, whereas CD107aresponses were similarly elevated to all antigens with severe disease. Further,S1 was also immunodominant for CD8+T cell responses, however IFN-andCD107a were predominantin severe disease in contrast to CD4+responses. Thus, S1-specific CD4+T cell responses in severe disease were unique with increased levels of the pro-inflammatory effector cytokine TNF-compared to mild disease controls, other antigens, and CD8+T cells.Lastly, we show that CD4+TNF+responses inversely correlated with absolute CD4+T cell counts in severe disease. Together, these findings revealthat the immunodominant SARS-CoV-2 S1 protein elicits a strong TNF-response from CD4+T cells that subverts the host T cell response. Our findings suggest that severe COVID-19 infection withpersistentS1-specific TNF-production from CD4+T cells more closely models chronic TNF-exposure, resulting in T cell 14hyporesponsivenessand dysfunction. In addition to anti-TNF-blockade agents, we found that low dose exogenous IL-2 also rescued S1-specific proliferative responses in the setting of low IL-2 frequencies that significantly increasedafter 6 days in the presence of TNF-blockade. Together, thesedata point to a relative IL-2-deficient state in severe COVID-19 disease that is TNF--dependent. Our studies show that TNF-/TNFRI-dependent apoptosis of CD4+T cells via AICD as amajormechanism contributing to CD4+lymphopeniain severe SARS-CoV-2 infection. We also observed that TNFRI-mediated apoptosis in CD4+T cells in severe COVID-19 was associated with increased surface expression of other activation markers such as CD95 (Fas) and CD38, and to a lesser extent PD-1, as previouslyreported in HIV infection(46, 47). We also observed that blockade of the Fas/FasL pathway, the major apoptotic pathway in HIV infection, also rescued CD4+T cells from AICD, though to a lesser extent than TNF-(22, 48).Our RNAseq studies also demonstrated that TNF-blockade significantly reduced expression of Type-1 cytokines including TNF-itself, NFB signaling and  FasL, consistent with the significant rescue of S1 re-stimulated CD4+T cells from AICD. Taken together, our findings support highlevels of TNF-/TNFRI-dependent apoptosis of CD4+T cells through AICD in severe COVID-19 disease that contributes to lymphopenia.We evaluated lungresidentT cells from an explanted lung (severe COVID-19) undergoing lung transplantation and found a similar diminutionin the CD4+/CD8+ratio in lung parenchymal and BAL cells, similar to PBMC. We further assessed BAL samples from fourLTRs with recent severe COVID infectionand had similar findings of reduced CD4+frequencies in the lung, along with a similar hierarchy of increased CD4+S1-specific TNF-production, that was increased in both the LP and BAL compartments compared to the PBMC. In summary, we show that the CD4+T cell immunodominant response to S1 during severe COVID induces high TNF-levels resulting in autocrineTNF-/TNFRI-dependent impaired CD4+proliferation and susceptibility to AICD. We further found that high autologous CD4+TNF-production correlated with a predominant CD4+lymphopenia during severe COVID disease, which we show is associated with increased mortality.Importantly, lung resident T cells produce elevated TNF-along with reduced CD4+T cell numbers.
Tags: иммунитет, коронавирус, статьи
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