The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.
Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.

h4>Background: /h4> T lymphocyte subsets with correlative cytokines, albumin to globulin ratio (AGR) and neutrophil to lymphocyte ratio (NLR), have been linked to inflammatory indicators of immune response and prognosis in various cancer types. The aim of this study was to determine the utility of these biomarkers in predicting the immunological benefits of Ganoderma spore powder in post-operative patients with breast and lung cancer. h4>Methods: /h4>: We prospectively evaluated 120 consecutive breast and lung cancer patients with or without Ganoderma spore powder. T lymphocyte subsets, as well as relative cytokines were detected and assessed by Pearson correlation analysis. The relationships between AGR and NLR with ganoderma spore powder treatment and prognosis were analyzed using Kaplan–Meier and Cox regression methods. h4>Results: /h4>: The prevalence of CD3+, CD4+ and CD4+/CD8+, CD3+HLADR-, CD4+HLADR- and CD8+HLADR- cell types was higher in the ganderma spore treated group compared to untreated controls. In addition, the percentage of CD4+CD25+Treg, CD3+HLADR+, CD4+HLADR+ and CD8+HLADR+ cell types was lower in the treated group. IL-2 and IL-12 frequencies were significantly higher during the treatment period which negatively impacted levels of IL-10. Other immunosuppressive factors such as COX2, TGF- 1 and HIF-1A had higher prevalence in non-treated patients. Correlation analysis showed several correlations between the biomarkers, specifically between IL-6 and TGF- 1, CD28 and IL-12R, TGF- 1 and Foxp3, IL-10 and IL-12R with COX2, Foxp3 and CD8, IL-10 and CD28 with IL-12R, COX2 and CD8, IL-12R with COX2, CD3 with CD4 and CD8. A positive relationship was also observed between IL-2 and TGF- 1. Conversely, IL-2 was negatively related to CD3, and HIF-1 negatively related with CD4, CD28 and CD3. Kaplan–Meier analysis suggested that low AGR/high NLR was related to poor progression free survival (PFS, HR=1.572, P=0.038/HR=2.064, P=0.042). A combination of high AGR and low NLR that predicted treatment benefits was also associated with PFS (HR=0.661, P=0.033/HR=1.044, P=0.048). h4>Conclusions: /h4>: Our findings show that T lymphocyte subsets predominately combined with relevant cytokines and AGR/NLR inflammatory predictors may help to identify patients most likely to benefit from the immunological enhancements from Ganoderma spore powder treatment.

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.