An off switch for helminth immunityGroup 2 innate lymphoid cells (ILC2s) are involved in responses to helminths, viruses, and allergens. Moriyama et al. found that ILC2s interact with the nervous ...system to modulate helminth immunity. ILC2s from the small intestine expressed the β2-adrenergic receptor (β2AR), which normally interacts with the neurotransmitter epinephrine. Inactivating β2AR resulted in lower helminth burden and more ILC2s, eosinophils, and type 2 cytokine production in mice. Conversely, treatment of helminth-infected mice with a β2AR agonist enhanced worm burden and reduced proliferation of ILC2s. Thus, β2AR negatively regulates ILC2-driven protective immunity.Science, this issue p. 1056The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the β2-adrenergic receptor (β2AR) and colocalize with adrenergic neurons in the intestine. β2AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, β2AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the β2AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation.
Full text
Available for:
BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota
. In mammals, changes in the composition of the ...microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases
. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders
. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Memory B cells are essential for generating rapid and robust secondary antibody responses. It has been thought that the unique cytoplasmic domain of IgG causes the prompt activation of ...antigen-experienced IgG memory B cells. To assess this model, we have generated a mouse containing IgG1 B cells that have never encountered antigen. We found that, upon challenge, antigen-experienced IgG1 memory B cells rapidly differentiated into plasma cells, whereas nonexperienced IgG1 B cells did not, suggesting the importance of the stimulation history. In addition, our results suggest that repression of the Bach2 transcription factor, which results from antigen experience, contributes to predisposition of IgG1 memory B cells to differentiate into plasma cells.
•IgG1 tail alone cannot explain robust antibody production•Expression of Bach2 is decreased in IgG1 memory B cells•Repression of Bach2 contributes to robust antibody production•mTOR signaling is involved in Bach2 repression
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antibody titers against SARS-CoV-2 slowly wane over time. Here, we examined how time affects antibody potency. To assess the impact of antibody maturation on durable neutralizing activity against ...original SARS-CoV-2 and emerging variants of concern (VOCs), we analyzed receptor binding domain (RBD)-specific IgG antibodies in convalescent plasma taken 1–10 months after SARS-CoV-2 infection. Longitudinal evaluation of total RBD IgG and neutralizing antibody revealed declining total antibody titers but improved neutralization potency per antibody to original SARS-CoV-2, indicative of antibody response maturation. Neutralization assays with authentic viruses revealed that early antibodies capable of neutralizing original SARS-CoV-2 had limited reactivity toward B.1.351 (501Y.V2) and P.1 (501Y.V3) variants. Antibodies from late convalescents exhibited increased neutralization potency to VOCs, suggesting persistence of cross-neutralizing antibodies in plasma. Thus, maturation of the antibody response to SARS-CoV-2 potentiates cross-neutralizing ability to circulating variants, suggesting that declining antibody titers may not be indicative of declining protection.
Display omitted
•Qualitative changes in plasma neutralizing antibody are longitudinally analyzed•Affinity-matured antibodies with resistance to variants are durably maintained•Neutralizing potency and breadth to SARS-CoV-2 variants increase with time•Serological immunity evolves with time to counter SARS-CoV-2 variants
Antigenic drifts in SARS-CoV-2 variants permit escape from neutralizing antibody in COVID-19 convalescent plasma. Moriyama et al. reveal the evolution of serological immunity with time that counters SARS-CoV-2 variants via affinity maturation and durable elicitation of IgG antibodies that are resistant to viral escape.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP ...can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Group 2 innate lymphoid cells (ILC2s) regulate immunity, inflammation, and tissue homeostasis. Two distinct subsets of ILC2s have been described: steady-state natural ILC2s and inflammatory ILC2s, ...which are elicited following helminth infection. However, how tissue-specific cues regulate these two subsets of ILC2s and their effector functions remains elusive. Here, we report that interleukin-33 (IL-33) promotes the generation of inflammatory ILC2s (ILC2INFLAM) via induction of the enzyme tryptophan hydroxylase 1 (Tph1). Tph1 expression was upregulated in ILC2s upon activation with IL-33 or following helminth infection in an IL-33-dependent manner. Conditional deletion of Tph1 in lymphocytes resulted in selective impairment of ILC2INFLAM responses and increased susceptibility to helminth infection. Further, RNA sequencing analysis revealed altered gene expression in Tph1 deficient ILC2s including inducible T cell co-stimulator (Icos). Collectively, these data reveal a previously unrecognized function for IL-33, Tph1, and ICOS in promoting inflammatory ILC2 responses and type 2 immunity at mucosal barriers.
•IL-33 promotes inflammatory ILC2s•Tph1 is upregulated in ILC2s upon activation in an IL-33-dependent manner•Il7rCre/+Tph1flox/flox mice are highly susceptible to helminth infections•Tph1 regulates inflammatory ILC2 responses during helminth infection
IL-33 is a potent activator of type 2 immune responses via the stimulation of ILC2s, but the downstream pathways triggered in these cells are poorly defined. Flamar and colleagues show that IL-33 controls tryptophan hydroxylase 1 expression in ILC2s, which is required for type 2 immunity against worm infections.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The coronavirus disease 2019 (COVID-19) pandemic is ongoing because of the repeated emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, highlighting the importance of ...developing vaccines for variants that may continue to emerge. In the present review, we discuss humoral immune responses against SARS-CoV-2 with a focus on the antibody breadth to the variants. Recent studies have revealed that the temporal maturation of humoral immunity improves the antibody potency and breadth to the variants after infection or vaccination. Repeated vaccination or infection further accelerates the expansion of the antibody breadth. Memory B cells play a central role in this phenomenon, as the reactivity of the B-cell antigen receptor (BCR) on memory B cells is a key determinant of the antibody potency and breadth recalled upon vaccination or infection. The evolution of memory B cells remarkably improves the reactivity of BCR to antigenically distinct Omicron variants, to which the host has never been exposed. Thus, the evolution of memory B cells toward the variants constitutes an immunological basis for the durable and broad control of SARS-CoV-2 variants.
Various antibody therapeutics has been developed for the treatment and suppression of the 2019 outbreak of novel coronavirus（SARS-CoV-2）infection. A major limitation in the development of SARS-CoV-2 ...neutralizing antibodies is the occurrence and spread of escape variants that have mutations in the spike glycoprotein. The coronaviruses are carried by various wild animals, domestic animals, and pets, and there have been cases of Severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus transmission from animals to people, resulting in a large spread of infection in people. There is also a possibility that cross-species transmission of SARS-CoV-2 may occur in the future. Considering these factors, the development of antibody therapeutics with broad cross-reactivity against SARS-CoV-2 variants and other coronaviruses is required.
Many variants of SARS-CoV-2 have emerged, and decreased neutralizing antibodies after vaccination and breakthrough infections have become a problem. The importance of monitoring titers of ...neutralizing antibodies is getting higher. We enrolled 146 COVID-19 patients, who were thought to be infected with Wuhan-hu-1 or D614G strains, and examined the time course of neutralizing titers against six concerning strains (Wuhan-hu-1, Alpha, Beta, Gamma, Kappa, and Delta) using newly developed ELISA. The acquisition of neutralizing titer was positively associated with disease severity. Immune evasions were observed approximately 20 to 30% for Alpha, Kappa, and Delta variant, and 40 to 45% for Beta and Gamma variant. The titers against all strains decreased over time, and interestingly, while titers against Wuhan-hu-1 decreased by 23%, those to Delta variant decreased by 70%. Our simple, cost-effective, and non-hazardous system will be applicable to process numerous samples, such as monitoring titers against prevalent strains after infection or vaccination.
•Newly developed ELISA reflects the results of authentic virus neutralizing assay.•The neutralizing titers were positively and clearly correlated with disease severity.•Immune evasion was observed all variant strains, including Kappa and Delta variants.•The neutralizing titer against the infected Wuhan-hu-1 decreased 23% in two months.•The neutralizing titers against Alpha, Gamma, and Delta variants decreased faster.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Serological tests for detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Abs in blood are expected to identify individuals who have acquired immunity against SARS-CoV-2 ...and indication of seroprevalence of SARS-CoV-2 infection. Many serological tests have been developed to detect Abs against SARS-CoV-2. However, these tests have considerable variations in their specificity and sensitivity, and whether they can predict levels of neutralizing activity is yet to be determined. This study aimed to investigate the kinetics and neutralizing activity of various Ag-specific Ab isotypes against SARS-CoV-2 in serum of coronavirus disease 2019 (COVID-19) patients confirmed via PCR test. We developed IgG, IgM, and IgA measurement assays for each Ag, including receptor-binding domain (RBD) of spike (S) protein, S1 domain, full-length S protein, S trimer, and nucleocapsid (N) domain, based on ELISA. The assays of the S protein for all isotypes showed high specificity, whereas the assays for all isotypes against N protein showed lower specificity. The sensitivity of all Ag-specific Ab isotypes depended on the timing of the serum collection and all of them, except for IgM against N protein, reached more than 90% at 15-21 d postsymptom onset. The best correlation with virus-neutralizing activity was found for IgG against RBD, and levels of IgG against RBD in sera from four patients with severe COVID-19 increased concordantly with neutralizing activity. Our results provide valuable information regarding the selection of serological test for seroprevalence and vaccine evaluation studies.
PDF
