COVID-19 vaccination influences subtypes of γδ-T cells during pregnancy.

Up to now, there has been insufficient clinical data to support the safety and effects of vaccination on pregnancy post COVID-19 vaccination. The γδ-T cells are considered an important component in the immune system to fight against viral infection and exhibit critical roles throughout the pregnancy period. However, the immunological roles of γδ-T cells in pregnant women with the COVID-19 vaccination remain unclear. Therefore, the objective of this study is to investigate the alteration of frequency and expression pattern of activation receptors and inhibitory receptors in γδ-T cell and its subsets in peripheral blood samples collected from non-pregnant vaccinated women, vaccinated pregnant women, and unvaccinated pregnant women. Our findings indicated that the frequency of CD3+γδ-T+ cells is lower in vaccinated pregnant women than in unvaccinated pregnant women. But no significant difference was found in the frequency of CD3+γδ-T+ cells between non-pregnant vaccinated women and vaccinated pregnant women. In addition, there were no significant differences in the frequencies of CD3+γδ-T+Vδ1+T cells, CD3+γδ-T+Vδ2+T cells, CD3+γδ-T+Vδ1-Vδ2-T cells, and Vδ1+T cell/Vδ2+T cell ratio between the pregnant women with or without COVID-19 vaccination. Similar results were found after comparing non-pregnant and pregnant women who received the COVID-19 vaccine. However, there was a significant difference in the fraction of Vδ1-Vδ2-T cells in CD3+γδ-T+ cells between non-pregnant vaccinated women and vaccinated pregnant women. The frequency of NKG2D+ cells in Vδ2+T cells was not significantly different in the vaccinated pregnant women when compared to that in unvaccinated pregnant women or non-pregnant vaccinated women. But the percentage of NKG2D+ cells in Vδ1+T cells was the lowest in pregnant women after COVID-19 vaccination. Furthermore, down-regulation of NKP46 and NKP30 were found in Vδ2+T and Vδ1+T cells in the vaccinated pregnant women, respectively. After the vaccination, up-regulation of PD-1 expression in Vδ1+T cells and Vδ2+T cells indicated γδ-T cells could respond to COVID-19 vaccination and display an exhausted phenotype following activation. In conclusion, COVID-19 vaccination influences subtypes of γδ-T cells during pregnancy, but the side effects might be limited. The phenotypical changes of Vδ1+T cells and Vδ2+T cells will be a promising predictor for evaluating the clinical outcome of the COVID-19 vaccine.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape.

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.

The legacy of maternal SARS-CoV-2 infection on the immunology of the neonate.

Despite extensive studies into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the effect of maternal infection on the neonate is unclear. To investigate this, we characterized the immunology of neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy. Here we show that maternal SARS-CoV-2 infection affects the neonatal immune system. Despite similar proportions of B cells, CD4+ T cells and CD8+ T cells, increased percentages of natural killer cells, Vδ2+ γδ T cells and regulatory T cells were detected in neonates born to mothers with recent or ongoing infection compared with those born to recovered or uninfected mothers. Increased plasma cytokine levels were also evident in neonates and mothers within the recent or ongoing infection group. Cytokine functionality was enhanced in neonates born to SARS-CoV-2-exposed mothers, compared to those born to uninfected mothers. In most neonates, this immune imprinting was nonspecific, suggesting vertical transmission of SARS-CoV-2 is limited, a finding supported by a lack of SARS-CoV-2-specific IgM in neonates despite maternal IgG transfer.

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System.

Gamma-delta (γδ) T cells are a subset of T cells that promote the inflammatory responses of lymphoid and myeloid lineages, and are especially vital to the initial inflammatory and immune responses. Given the capability to connect crux inflammations of adaptive and innate immunity, γδ T cells are responsive to multiple molecular cues and can acquire the capacity to induce various cytokines, such as GM-CSF, IL-4, IL-17, IL-21, IL-22, and IFN-γ. Nevertheless, the exact mechanisms responsible for γδ T cell proinflammatory functions remain poorly understood, particularly in the context of the central nervous system (CNS) diseases. CNS disease, usually leading to irreversible cognitive and physical disability, is becoming a worldwide public health problem. Here, we offer a review of the neuro-inflammatory and immune functions of γδ T cells, intending to understand their roles in CNS diseases, which may be crucial for the development of novel clinical applications.

Commensal Microbiome Expands Tγδ17 Cells in the Lung and Promotes Particulate Matter-Induced Acute Neutrophilia.

Particulate matter (PM) induces neutrophilic inflammation and deteriorates the prognosis of diseases such as cardiovascular diseases, cancers, and infections, including COVID-19. Here, we addressed the role of γδ T cells and intestinal microbiome in PM-induced acute neutrophilia. γδ T cells are a heterogeneous population composed of Tγδ1, Tγδ2, Tγδ17, and naïve γδ T cells (TγδN) and commensal bacteria promote local expansion of Tγδ17 cells, particularly in the lung and gut without affecting their Vγ repertoire. Tγδ17 cells are more tissue resident than Tγδ1 cells, while TγδN cells are circulating cells. IL-1R expression in Tγδ17 cells is highest in the lung and they outnumber all the other type 17 cells such as Th17, ILC3, NKT17, and MAIT17 cells. Upon PM exposure, IL-1ß-secreting neutrophils and IL-17-producing Tγδ17 cells attract each other around the airways. Accordingly, PM-induced neutrophilia was significantly relieved in γδ T- or IL-17-deficient and germ-free mice. Collectively, these findings show that the commensal microbiome promotes PM-induced neutrophilia in the lung via Tγδ17 cells.

How to Train Your Dragon: Harnessing Gamma Delta T Cells Antiviral Functions and Trained Immunity in a Pandemic Era.

The emergence of viruses with pandemic potential such as the SARS-CoV-2 coronavirus causing COVID-19 poses a global health challenge. There is remarkable progress in vaccine technology in response to this threat, but their design often overlooks the innate arm of immunity. Gamma Delta (γδ) T cells are a subset of T cells with unique features that gives them a key role in the innate immune response to a variety of homeostatic alterations, from cancer to microbial infections. In the context of viral infection, a growing body of evidence shows that γδ T cells are particularly equipped for early virus detection, which triggers their subsequent activation, expansion and the fast deployment of antiviral functions such as direct cytotoxic pathways, secretion of cytokines, recruitment and activation of other immune cells and mobilization of a trained immunity memory program. As such, γδ T cells represent an attractive target to stimulate for a rapid and effective resolution of viral infections. Here, we review the known aspects of γδ T cells that make them crucial component of the immune response to viruses, and the ways that their antiviral potential can be harnessed to prevent or treat viral infection.

Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients.

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.

The Aging of γδ T Cells.

In the coming decades, many developed countries in the world are expecting the "greying" of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently-resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer.