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CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen-antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR- counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging.". [ABSTRACT FROM AUTHOR]

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

In mice, the ability of naive T (T N ) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8 + T N cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3 + T N cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3 + T N cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3 + T N cells were transcriptionally equivalent to murine CXCR3 + T N cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8 + T cells., (Copyright © 2019 The Authors.)

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4 + T-cell activity. However, to date, the characterization of the CD4 + regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4 + FOXP3 + cells in circulation owing to a specific expansion of thymically-derived FOXP3 + HELIOS + Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp 620 (rs2476601C>T) on Treg frequency. Trp 620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3 + Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3 + Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders., (Copyright © 2019 Ferreira, Castro Dopico, Oliveira, Rainbow, Yang, Trzupek, Todd, McNeill, Steri, Orrù, Fiorillo, Crouch, Pekalski, Cucca, Tree, Vyse, Wicker and Todd.)

Genome Wide Association Studies (GWAS) have mapped thousands of genetic variants associated with complex disease risk and regulating quantitative traits, thus exploiting an unprecedented high-resolution genetic characterization of the human genome. A small fraction (3.7%) of the identified associations is located in untranslated regions (UTRs), and the molecular mechanism has been elucidated for few of them. Genetic variations at UTRs may modify regulatory elements affecting the interaction of the UTRs with proteins and microRNAs. The overall functional consequences include modulation of messenger RNA (mRNA) transcription, secondary structure, stability, localization, translation, and access to regulators like microRNAs (miRNAs) and RNA-binding proteins (RBPs). Alterations of these regulatory mechanisms are known to modify molecular pathways and cellular processes, potentially leading to disease processes. Here, we analyze some examples of genetic risk variants mapping in the UTR regulatory elements. We describe a recently identified genetic variant localized in the 3'UTR of the TNFSF13B gene, associated with autoimmunity risk and responsible of an increased stability and translation of TNFSF13B mRNA. We discuss how the correct use and interpretation of public GWAS repositories could lead to a better understanding of etiopathogenetic mechanisms and the generation of robust biological hypothesis as starting point for further functional studies. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Evolution and Genomics > Computational Analyses of RNA RNA in Disease and Development > RNA in Disease., (© 2018 Wiley Periodicals, Inc.)

CD4 + regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8 + human leukocyte antigen-antigen D related (HLADR) + T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8 + HLADR + T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8 + HLADR + T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR - counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8 + HLADR + T cells from elderly persons are analyzed. In accordance with this finding, CD8 + HLADR + T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8 + regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging."

Background: HIV-associated immunodeficiency is related to loss of CD4 + T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4 + T cells/μL. CD8 + CD28 - CD127 lo CD39 + T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients., Objectives: We sought to analyze the frequency of CD8 + CD28 - CD127 lo CD39 + Treg cells in the circulation of HIV-infected patients., Methods: The frequency of circulating CD8 + CD28 - CD127 lo CD39 + Treg cells was analyzed and correlated with viral load and CD4 + T-cell counts/percentages in 93 HIV-1-infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus-infected patients (n = 17), and healthy donors (n = 173)., Results: HIV-infected patients had increased circulating levels of functional CD8 + CD28 - CD127 lo CD39 + Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4 + T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non-AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant., Conclusion: HIV infection induces remarkable expansion of CD8 + CD28 - CD127 lo CD39 + Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)