T cells are implicated in the pathophysiology of preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Specifically, maternal decidual T cells infiltrate the chorioamniotic membranes in chronic chorioamnionitis (CCA), a placental lesion considered to reflect maternal anti-fetal rejection, leading to preterm labor and birth. However, the phenotype and TCR repertoire of decidual T cells in women with preterm labor and CCA have not been investigated. In this study, we used phenotyping, TCR sequencing, and functional assays to elucidate the molecular characteristics and Ag specificity of T cells infiltrating the chorioamniotic membranes in women with CCA who underwent term or preterm labor. Phenotyping indicated distinct enrichment of human decidual effector memory T cell subsets in cases of preterm labor with CCA without altered regulatory T cell proportions. TCR sequencing revealed that the T cell repertoire of CCA is characterized by increased TCR richness and decreased clonal expansion in women with preterm labor. We identified 15 clones associated with CCA and compared these against established TCR databases, reporting that infiltrating T cells may possess specificity for maternal and fetal Ags, but not common viral Ags. Functional assays demonstrated that choriodecidual T cells can respond to maternal and fetal Ags. Collectively, our findings provide, to our knowledge, novel insight into the complex processes underlying chronic placental inflammation and further support a role for effector T cells in the mechanisms of disease for preterm labor and birth. Moreover, this work further strengthens the contribution of adaptive immunity to the syndromic nature of preterm labor and birth.
Copyright © 2023 by The American Association of Immunologists, Inc.

Acetylcholine (ACh), as a ligand of nicotinic acetylcholine receptors (nAChRs), plays a key role in the cholinergic anti-inflammatory pathway; however, its role in the immunoglobulin A (IgA) response remains unknown. Therefore, the present study aimed to investigate the role of ACh in the intestinal biomarkers involved in IgA synthesis and the polymeric immunoglobulin receptor (pIgR) involved in IgA transcytosis. Groups of mice were administered GTS-21 (an α7nAChR agonist) or mecamylamine (a non-selective nAChR antagonist) intraperitoneally for 7 days. Intestinal fluids were used for antibody concentration assessment by ELISA, cell suspensions from Peyer's patches and the lamina propria were obtained for flow cytometric analysis of plasma cells, and CD4+ T-cells expressing intracellular transforming growth factor (TGF)-β and IgA-producing interleukin (IL)-4, -5, -6 and -10, and isolated epithelial cells to determine the levels of pIgR mRNA using reverse transcription-quantitative PCR. Regarding to the untreated control group, the concentration of IgA was reduced in the mecamylamine group and unaltered in the GTS-21 group while IgM levels exhibited no differences; the percentage of IgA+ plasma cells from Peyer's patches and the lamina propria, and the percentage of TGF-β+/CD4+ T-cells from Peyer's patches were greater in the GTS-21-group. In both treatment groups, the percentages of IgM+ plasma cells and IL-6+/IL-10+ CD4+ T cells were greater in both compartments; pIgR mRNA expression levels decreased in epithelial cells. The percentage of IL-4 CD4+ T-cells were greater in Peyer's patches and lower in the lamina propria in the mecamylamine group, and the percentage of IL-5 CD4+ T-cells in the lamina propria were decreased in both treatment groups. These findings require further examination to address the impact of cholinergic modulation on IgA-transcytosis via pIgR. The present study may be an experimental reference for clinical trials that address the role of nicotinic system in intestinal dysfunctions as postoperative ileus.
Copyright: © Carrizales-Luna et al.

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax-a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)-induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.
Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT.