Клеточный и гуморальный ответ -коррелируют

chuka_lis — 30.01.2022 При ковиде, изменения в ответ на инфекцию, происходящие с клеточным иммунитетом (Т клетки) положительно коррелируют с гуморальным ответом на вирус (нейтрализующие антитела).
Клеточный иммунитет после инфекции и прививки слегка отличается. После инфекции, спустя время, среди лимофицтов помощников, чувствительных к коронавирусу, начинают преобладать популяции, продуцирующие ФНО-альфа. Преобладание таких лимфоцитов связано с возрастом, полом и тяжестью ковида (т. е их больше у тех кто старше, у мужчин, и у тех, кто болел тяжелее).
После прививки, или после прививки и инфекции, присутствуют Т-лимофциты, производящие в ответ на встречу с коронавирусом и интерферон, и ФНО. У тех кто привился после болезни, количество Тлимфоцитов, производящих ФНО, увеличилосьу меренно, а вто призводящих интерферон- значительно.
"Чувствительные" Т-лимфоциты, как и антитела, сохранялись до 7 месяцев после ковида (или прививки).
We characterized SARS-CoV-2-specific CD4⁺ T cells in a longitudinal cohort of 109 COVID-19 outpatients. The quality of the SARS-CoV-2-specific CD4⁺ response shifted from cells producing IFNγ to TNFα⁺ from five days to four months post-enrollment, with IFNγ^-IL21^-TNFα⁺ CD4⁺ T cells the predominant population detected at later timepoints. Greater percentages of IFNγ^-IL21^-TNFα⁺ CD4⁺ T cells on day 28 correlated with SARS-CoV-2 neutralizing antibodies measured seven months post-infection (ρ=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosted both IFNγ and TNFα producing, spike protein-specific CD4⁺ T cells. These data suggest that SARS-CoV-2-specific, TNFα-producing CD4⁺ T cells may play an important role in antibody maintenance following COVID-19.
In this longitudinal study of SARS-CoV-2-specific CD4⁺ T cell magnitude and quality in outpatients enrolled in a Phase 2 clinical trial of Peginterferon Lambda, we identified a shift in the quality of the SARS-CoV-2-specific CD4⁺ T cell response from IFNγ^-producing at early timepoints to TNFα-producing response at later timepoints (≥D28). IFNγ^-IL21^-TNFα⁺ CD4⁺ T cells were the predominant cytokine-producing T cell population following infection and sustained up to month ten post-enrollment. Percentages of TNFα-producing CD4⁺ T cells were positively correlated with AIM⁺ T cell populations and activated ICOS⁺ cTfh cells. Higher percentages of TNFα-producing CD4⁺ T cells and ICOS⁺ cTfh cells were more commonly found in participants who had experienced a more severe infection and were positively associated with higher levels of the chemokine CCL7/MCP-3 at the time of enrollment. Percentages of IFNγ^- IL21^-TNFα⁺CD4⁺ T cells, along with activated ICOS⁺ cTfh cells, were positively correlated with neutralizing antibodies measured up to seven months post-enrollment. These cells were only modestly boosted following mRNA vaccination in comparison to other cellular populations, including S protein-specific AIM⁺ cTfh cells and IFNγ⁺-producing CD4⁺ T cells.
Polyfunctional CD4⁺ Th1 cells producing IFNγ and TNFα (along with IL2) have been thought to be important in response to some viral infections, including HIV and influenza (Betts et al., 2006; Lin et al., 2015; Seder et al., 2008). This polyfunctional Th1 cytokine profile has been observed among convalescent mild and severe COVID-19 patient in several studies (Braun et al., 2020; Breton et al., 2021; Grifoni et al., 2020; Neidleman et al., 2020; Peng et al., 2020; Rydyznski Moderbacher et al., 2020; Sekine et al., 2020; Weiskopf et al., 2020; Zuo et al., 2021), although the importance of this versus other cytokine-producing populations of circulating SARS-CoV-2-specific CD4⁺ T cells remains unclear. However, many of these studies were cross-sectional in nature, with significant heterogeneity observed (Rydyznski Moderbacher et al., 2020; Sekine et al., 2020; Tan et al., 2021; Weiskopf et al., 2020; Zhou et al., 2020). In the present study, we detected a substantial proportion of CD4⁺ T cells producing both IFNγ and TNFα (along with IL2) that peaked in percentage early in convalescence. In contrast, at later timepoints, TNFα-producing cells, without IFNγ, were the predominant population detected in our ICS assay. This finding is particularly relevant given the development of clinical assays designed to detect SARS-CoV-2-specific T cell responses via measurement of IFNγ release (Murugesan et al., 2021), and suggest that assays measuring SARS-CoV-2-specific TNFα production could be considered as a tool to define previous exposure to SARS-CoV-2.
In addition to measuring SARS-CoV-2-specific T cells by ICS, we also utilized an AIM assay employing markers for both CD4⁺ T cells and cTfh cells, and similar with published reports (Dan et al., 2021; Jung et al., 2021), detected SARS-CoV-2-specific AIM⁺ CD4⁺ T cells up to ten months post-enrollment. Moreover, we observed that cytokine-producing CD4⁺ T cell populations -in particular, TNFα single positive cells - positively and significantly correlated with AIM⁺ CD4⁺ T cells, activated ICOS⁺ cTfh cells, and AIM⁺ cTfh cells. Given their central-memory like phenotype, we speculate that SARS-CoV-2-specific TNFα single positive cells may represent a memory pool of either memory Th1 or Tfh cells (Lönnberg et al., 2017) or stem-cell like memory cells (Jung et al., 2021); molecular work is ongoing to identify transcription factors that might help elucidate the ontogeny of these cells. Our observations that several plasma proteins, including the chemokine MCP-3/CCL7, measured at the time of infection strongly correlate with higher percentages of these cells on D28 suggests that a robust innate immune response at the time of infection may lead to greater expansion of this cell subset; however, this immune activation may also represent a double-edged sword given its association with early disease progression (Hu et al., 2021; Merad & Martin, 2020; Yang et al., 2020). No correlation was observed between IL21^-producing CD4⁺ T cells and cTfh cells. This was unexpected given that IL21 is thought to be a canonical cTfh cytokine (Crotty, 2019; Eto et al., 2011; Hale & Ahmed, 2015; Rasheed et al., 2013). Furthermore, we were unable to detect any antigen-specific IL10 production. One possible explanation for these findings is that our ICS assay was not optimized to detect SARS-CoV-2-specific IL21 or IL10 production, although we and others have successfully used a similar approach to detect these CD4⁺ T cell cytokines in other settings (Jagannathan et al., 2014). Alternatively, it is possible that cTfh are not representative of germinal center Tfh in this setting, or that these cytokines may not be induced in the SARS-CoV-2-specific CD4⁺ T cell compartment following infection, although this will require further validation in other cohorts and settings.
Although several studies have reported correlations between SARS-CoV-2-specific CD4⁺ T cell responses and SARS-CoV-2-specific antibody titers measured at either the peak of response or at concurrent timepoints (Boppana et al., 2021; Dan et al., 2021; Ni et al., 2020; Peng et al., 2020; Rydyznski Moderbacher et al., 2020; Zuo et al., 2021), there is limited data correlating infection-induced CD4⁺ T cell responses with antibodies measured prospectively. Although SARS-CoV-2-specific, polyfunctional IFNγ and TNFα co-producing CD4⁺ T cells at D5 correlated with the neutralizing antibody response at D28 by Spearman correlation, this finding was not significant after multiple comparison correction. In contrast, we observed that TNFα-single positive cells measured on D28, rather than polyfunctional, IFNγ and TNFα co-producing cells, were most strongly correlated with neutralizing antibodies measured seven months post-enrollment. We also observed a significant positive correlation between activated, ICOS⁺ cTfh cell percentages on D28 and neutralization antibodies on month seven. This suggests that SARS-CoV-2-specific TNFα-producing CD4⁺ T cells and activated cTfh cells measured weeks after infection may serve as a useful correlate to identify individuals who exhibit durable antibodies. Furthermore, additional characterization of these cellular populations would help identify strategies to determine whether boosting of this response could increase durability of neutralizing antibodies.
Given our study design, we were uniquely positioned to compare CD4⁺ T cell responses among previously infected study participants who did and did not receive two doses of a COVID-19 mRNA vaccine during follow-up. We found that mRNA vaccination particularly boosts S protein-specific CD4⁺ T cells that produce IFNγ, with or without TNFα, along with AIM⁺ cTfh cells. There was only modest boosting of TNFα single positive cells, and no boosting of MN protein–specific cells. These findings are consistent with a recent systems analysis of immune responses following the BNT162b2 mRNA vaccine (Arunachalam et al., 2021). In that study, Arunachalam and colleagues found that vaccination resulted in robust expansion of IFNγ^-producing CD4⁺ T cells, although they observed no significant correlation between levels of IFNγ producing CD4⁺ T cells and the neutralizing antibody response measured prospectively. In another study by Painter and colleagues, the percentage of antigen-specific cTfh cells prior to the second dose of mRNA vaccination correlated with post-second dose neutralizing antibody titers. In contrast, pre-second dose antigen-specific Th1 cells were less well correlated, suggesting distinct associations between Th populations and vaccine-elicited immune responses (Painter et al., 2021). Together, these data suggest that the quality of the CD4⁺ T cell response differs between natural infection and vaccination, although the downstream impact of different CD4⁺ T cell responses on the neutralizing antibody response and protective immunity remain unclear.
This study had some limitations. Half of the study participants in this trial received an investigational Type III IFN at the time of infection. However, in this study, this agent neither shortened the duration of viral shedding nor symptoms (Jagannathan et al., 2021), nor did we observe any significant impact on either innate (Hu et al., 2021) or adaptive (Chakraborty et al., 2021) immune responses between arms, allowing us to utilize data from both arms to improve statistical power. In addition, stratified analyses, and multivariate models adjusted for treatment arm as a covariate, confirmed pooled results. Although we would have liked to have assessed for correlations with protection against reinfection, only one participant had evidence of reinfection during follow-up. Future larger cohorts, and/or case/control designs, will be required to address this question. Finally, we only utilized data assessing responses to the original consensus strain, and do not present data on responses to variants. However, others have recently reported that infection-induced SARS-CoV-2 T cell responses have broad reactivity against viral variant proteins (Keeton et al., 2021; Tarke et al., 2021).
By providing insight into the shifting quality of the SARS-CoV-2-specific CD4⁺ T cell response following infection, how this is impacted by vaccination, and which features most strongly correlate with immune effector mechanisms, our study adds to our growing understanding of the memory T cell response to SARS-CoV-2. Given ongoing SARS-CoV-2 transmission and increasing risk of both re-infections and breakthrough infections following vaccination, identification of correlates of protective immunity remains critical in the design of next generation COVID-19 vaccination strategies.

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