Coronavirus disease 2019 (COVID-19), the current pandemic disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Type I and III interferons (IFNs) are innate ...cytokines that are important in the first-line defense against viruses. Similar to many other viruses, SARS-CoV-2 has evolved mechanisms for evading the antiviral effects of type I and III IFNs at multiple levels, including the induction of IFN expression and cellular responses to IFNs. In this review, we describe the innate sensing mechanisms of SARS-CoV-2 and the mechanisms used by SARS-CoV-2 to evade type I and III IFN responses. We also discuss contradictory reports regarding impaired and robust type I IFN responses in patients with severe COVID-19. Finally, we discuss how delayed but exaggerated type I IFN responses can exacerbate inflammation and contribute to the severe progression of COVID-19.
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.
In addition to CD4
T cells and neutralizing antibodies, CD8
T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19), an ongoing ...pandemic disease. In patients with COVID-19, CD8
T cells exhibiting activated phenotypes are commonly observed, although the absolute number of CD8
T cells is decreased. In addition, several studies have reported an upregulation of inhibitory immune checkpoint receptors, such as PD-1, and the expression of exhaustion-associated gene signatures in CD8
T cells from patients with COVID-19. However, whether CD8
T cells are truly exhausted during COVID-19 has been a controversial issue. In the present review, we summarize the current understanding of CD8
T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8
T cells in the context of activation and exhaustion. We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8
T cells and discuss long-term SARS-CoV-2-specific CD8
T-cell memory.
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.
During viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as "bystander activation." Cytokines, ...including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8
T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8
T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8
T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.
Hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for most cases of viral hepatitis. Infection by each type of virus results in a different typical natural ...disease course and clinical outcome that are determined by virological and immunological factors. HCV tends to establish a chronic persistent infection, whereas HAV does not. HBV is effectively controlled in adults, although it persists for a lifetime after neonatal infection. In this Review, we discuss the similarities and differences in immune responses to and immunopathogenesis of HAV, HBV and HCV infections, which may explain the distinct courses and outcomes of each hepatitis virus infection.
Background and Aims
Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly ...4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes TILs) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC).
Approach and Results
Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation.
Conclusion
4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.
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.
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