Galectin-3 is a 31 kD lectin that modulates T-cell responses through several mechanisms including apoptosis, T-cell receptor (TCR) cross-linking, and TCR down-regulation. We found patients with pancreatic ductal adenocarcinoma (PDA) responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDA vaccine developed post immunization neutralizing antibodies to galectin-3. We show that galectin-3 binds activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). Galectin-3-deficient mice exhibit improved CD8+ T-cell effector function, and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8+ T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells (pDC), which are superior to conventional dendritic cells (cDC) in activating CD8+ T cells. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell-directed immunotherapies should enhance the tumor-specific immune response.

Genetic and antigenic characterization established the uniqueness of this virus circulating in dogs.

BackgroundCancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.Methodology/Principal FindingsHigh and low avidity CD8+ T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4+Foxp3+CD25low tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.Conclusion/SignificanceDepletion of CD25low Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity.

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe clinical phenotype of SARS-CoV-2 infection that remains poorly understood. Methods Hospitalized children <18 years of age with suspected COVID-19 (N=53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the U.S. Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral RNA levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. Results The median ages for those with and without MIS-C were 8.7 years (IQR 5.5-13.9) and 2.2 years (IQR 1.1-10.5), respectively, (p=0.18) and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the two groups (median 63,848.25 copies/mL versus 307.1 copies/mL, p= 0.66); 75% of those with MIS-C were antibody positive compared to 44% without, p=0.026. Levels of 14 of 37 cytokines/chemokines (IL-1RA, IL-2RA, IL-6, IL-8, TNF-α, IL-10, IL-15, IL-18, MCP-1, IP-10, MIP-1α, MCP-2, MIP-1β, Eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (FDR<0.05; p<0.05). Conclusions The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt and Paschold et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C. Evolution of MIS-C as a new pediatric diseaseOver the past year, SARS-CoV-2 has been implicated in a variety of different disease processes. In addition to the respiratory syndrome now known as COVID-19, SARS-CoV-2 has also been implicated in formation of blood clots, rashes, neurological symptoms, and a post-infectious syndrome termed "long COVID." In sharp contrast to other respiratory viruses such as RSV and influenza, which cause a substantial disease burden in the pediatric population every year during the fall and winter months, the burden of disease for COVID-19 has fallen predominantly on adults.

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The aim of this study was to develop a method for objectively assessing the delivery of care to children with autism spectrum disorder (ASD) in the emergency department (ED). Methods: A case-control study of patients ages 2 to 18 years admitted to the hospital from January 2016 to January 2018. Cases were defined as patients with an International Classification of Diseases, Tenth Revision diagnosis of ASD or other pervasive developmental disorder (F84) in their medical record and were matched 1:1 with neurotypical controls. The primary outcome was ability to complete several core tasks clinically necessary within an ED visit and summarized into a Task Completion Index (TCI). Results: Overall, children with ASD had higher median TCIs of 0.25 (interquartile range [IQR] 0-0.45) versus 0 (IQR 0-0.25) when compared with children without ASD (p < 0.01). Children with ASD were 5 times more likely to have difficulty with triage vitals, 3 times more likely to require additional staff for peripheral intravenous placement, and 4 times more likely to experience delays or disruptions to their plan of care. The TCI was also associated with 8-fold increased odds of receiving pharmacologic or physical restraint. Conclusions: The TCI reflects difficulty accomplishing core tasks necessary to complete an ED visit. Children with ASD have higher TCIs than neurotypical controls, which puts them at higher risk for care disruptions. Evaluation of initiatives to improve quality of care for children with ASD should focus not only on metrics of overall experience and satisfaction but also how these initiatives affect the ability to effectively administer care.

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