During microbial infection, pre-existing memory CD8
T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. ...Studies in mouse models and human patients demonstrate bystander activation of memory CD8
T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8
T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8
T cells. In this Review, we describe the history of research on bystander CD8
T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.
Abstract
Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. Here we conduct ex vivo ...assays to evaluate SARS-CoV-2-specific CD4
+
and CD8
+
T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4
+
and CD8
+
T cells detected by activation-induced markers, the proportion of stem cell-like memory T (T
SCM
) cells is increased, peaking at approximately 120 DPSO. Development of T
SCM
cells is confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of T
SCM
cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19, thus support the feasibility of effective vaccination programs as a measure for COVID-19 control.
Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute ...liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.
Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress ...syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1β-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.
Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC ...class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1− cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.
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•SARS-CoV-2-specific CD8+ T cells are effector memory cells in convalescents•CCR7+CD45RA+ cells are increased among SARS-CoV-2-specific cells in the late phase•SARS-CoV-2-specific CD8+ T cells have fewer IFN-γ+ cells than flu-specific cells•PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional
T cell responses have been demonstrated in COVID-19 patients, but ex vivo phenotypes and functions of SARS-CoV-2-specific T cells remain unclear. Rha et al. examined SARS-CoV-2-specific CD8+ T cells in acute and convalescent COVID-19 patients using MHC class I multimers, finding that PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional.
Our understanding of adaptive immune responses in patients with coronavirus disease 2019 (COVID-19) is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is ...still insufficient.
We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19.
We performed RNA sequencing and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved PBMCs.
In RNA-sequencing analysis, the NK cells exhibited distinctive features compared with healthy donors, with significant enrichment of proinflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56dimCD16neg NK-cell population expanded in cryopreserved PBMCs from patients with COVID-19 regardless of disease severity, accompanied by decreased NK-cell cytotoxicity. The NK-cell population was rapidly normalized alongside the disappearance of unconventional CD56dimCD16neg NK cells and the recovery of NK-cell cytotoxicity in patients with mild COVID-19, but this occurred slowly in patients with severe COVID-19.
The current longitudinal study provides a deep understanding of the NK-cell biology in COVID-19.
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Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. ...However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.
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