T cell responses induced by SARS-CoV-2 mRNA vaccination are associated with clonal replacement

mRNA vaccines against the Spike glycoprotein of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2) elicit strong T-cell responses. However, it is unknown whether T cell clones induced by the first vaccination or newly generated T cell clones dominate responses to the secondary vaccination. Here, we analyzed the kinetic profile of Spike-reactive T-cell clones before the first dose, one week after the first and second dose, and four weeks after the second dose of the BNT162b mRNA vaccine. Interestingly, a new set of Spike-reactive CD8+ T cell clones exhibited the greatest expansion following secondary vaccination and replaced the clones that had responded to the primary vaccination. Single-cell mRNA/protein/TCR analysis revealed that the first-responder clones exhibited a terminally differentiated phenotype, whereas second-responder clones exhibited an actively proliferating phenotype. These results show that Spike-reactive T cell responses induced by repetitive mRNA vaccination are augmented and maintained by replacement with newly-generated clones with proliferative potential. One Sentence SummaryTCR repertoire analysis following mRNA vaccination against SARS-CoV-2 revealed the replacement of Spike-reactive T cell clones.

Transition of antibody titers after the SARS-CoV-2 mRNA vaccine in Japanese healthcare workers

Since February 2021, health care workers in Japan have been preferentially vaccinated with a messenger RNA vaccine (BNT162b2/Pfizer) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While many studies have confirmed that this vaccine is highly effective in reducing hospitalizations and deaths from coronavirus disease 2019 (COVID-19), antibody titers tend to decline at 3 months, leading to a risk of breakthrough infections. Thus, information is needed to support decision making regarding the third vaccination. In this study, we investigated transition of the anti-SARS-CoV-2 receptor-binding domain (RBD) IgG and neutralizing antibody titers of 41 vaccinated Japanese healthcare workers. Samples were collected seven times starting 1 week before vaccination until 6 months post-vaccination. Anti-SARS-CoV-2 RBD IgG levels peaked at 7 days after the booster, then declined over time and decreased to <10% at 6 months after the booster. Workers with low anti-SARS-CoV-2 RBD IgG levels also had low neutralizing antibody titers. These data support the active use of boosters for healthcare workers, especially for those with low anti-SARS-CoV-2 RBD IgG levels.

Breakdown of Mucosal Immunity in Gut by 2,3,7,8-Tetraclorodibenzo-\it{p}-dioxin (TCDD)

Objectives: Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut. Methods: Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed. Results: Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer’s patches (PPs) and mesenteric lymph nodes (LNs). Decreased IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA+ B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA+ cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs. Conclusions: These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.

Breakdown of mucosal immunity in gut by 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD)

<p><b>OBJECTIVES</b>Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut.</p><p><b>METHODS</b>Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed.</p><p><b>RESULTS</b>Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer's patches (PPs) and mesenteric lymph nodes (LNs). Decressed IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs.</p><p><b>CONCLUSIONS</b>These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.</p>

Comprehensive eene expression profile of acute lung injury induced by lipopolysacchande in mice / 中华创伤杂志

Objective To monitor the systemic gene expression profile in a murine model of li-popolysaccharide (LPS)-induced acute lung injury by the recently modified long serial analysis of gene expression (SAGE) so as to discuss the molecular mechanism of acute lung injury. Methods Acute lung injury was induced by intra-tracheal injection of LPS (25 mg/kg). Control mice were given normal saline in same volume. Animals were killed at 24 hours after the administration of LPS and lungs were harvested en bloc for SAGE study. Results A total of 24 670 tags representing 12 168 transcripts in the control mice and 26 378 tags representing 13 397 transcripts in the mice with lung injury were identified respectively. There were 11 transcripts increased more than 10 folds, 107 transcripts 5-10 folds and 2 121 transcripts 2-5 folds in the LPS-treated mice. But seven transcripts decreased to 1/10, 87 transcripts to 1/10-1/5 and 1 571 transcripts to 1/5-1/2. The most overexpressed genes in the lung injury mice mainly included serum amyloid A 3, metallothionein 2, lipocalin 2, cyclin-dependent kinase inhibitor 1A, lactate dehydrogenase 1 , melatonin receptor, SI00 calcium-binding protein A9 and natriuretic pep-tide precursor. Mitogen activated protein kinase 3, serum albumin, complement component 1 inhibitor, and ATP synthase were underexpressed in the lung injury mice. Conclusion The changes of various genes as well as some unreported genes have been confirmed in the LPS-induced acute lung injury. Further studies of these unreported genes are beneficial to better understanding the mechanism of acute lung injury and may provide useful markers for clinical diagnosis.