The molecules that define human regulatory T cells (Tregs) phenotypically and functionally remain to be fully characterized. We recently showed that activated human Tregs express mRNA for a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32). Here, using a GARP-specific mAb, we demonstrate that expression of GARP on activated Tregs correlates with their suppressive capacity.

Background Identification of the Th17 T cell subset as important mediators of host defense and pathology, prompted us to determine their susceptibility to HIV infection. Methods and Results We found that a sizeable portion of Th17 cells express HIV co-receptor CCR5 and produce very low levels of CCR5 ligands MIP-1α and MIP-1β. Accordingly, CCR5+ Th17 cells were efficiently infected with CCR5-tropic HIV and were depleted during viral replication in vitro. Remarkably, HIV+ individuals under treatment showed significantly reduced Th17 cells compared to HIV− subjects, regardless of their viral loads or CD4 numbers, whereas treatment naïve subjects had normal levels. However, there was a preferential reduction in CCR5+ T cells that were also CCR6+, which is expressed on all Th17 cells, as compared to CCR6−CCR5+ cells, in both treated and untreated HIV+ subjects. This observation suggests preferential targeting of CCR6+CCR5+ Th17 cells by CCR5-tropic viruses in vivo. Th17 cell levels also inversely correlated with activated CD4+ T cells in HIV+ individuals under treatment. Conclusion Our findings suggest a complex perturbation of Th17 subsets during the course of HIV-disease potentially through both direct viral infection and virus indirect mechanisms such as immune activation.

Chronic immune activation is a hallmark of HIV infection, yet the underlying triggers of immune activation remain unclear. Persistent antigenic stimulation during HIV infection may also lead to immune exhaustion, a phenomenon in which effector T cells become dysfunctional and lose effector functions and proliferative capacity. Several markers of immune exhaustion, such as PD-1, LAG-3, Tim-3, and CTLA-4, which are also negative regulators of immune activation, are preferentially upregulated on T cells during HIV infection. It is not yet clear whether accumulation of T cells expressing activation inhibitory molecules is a consequence of general immune or chronic HIV-specific immune activation. Importantly, however, in vitro blockade of PD-1 and Tim-3 restores HIV-specific T-cell responses, indicating potential for immunotherapies. In this review we discuss the evolution of our understanding of immune exhaustion during HIV infection, highlighting novel markers and potential therapeutic targets.

A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17+Treg cells differentiate from naïve precursors remains unclear. Here, we show that IL-17-producing T-cells can differentiate from CCR6+ naïve T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6+ naïve T cells are present in adult peripheral and umbilical cord blood and in both conventional T naïve (TN) and FOXP3+ naïve Treg (TNreg) subsets. IL-17+ cells derived from CCR6+ TNreg cells (referred to as IL-17+Treg) express FOXP3, but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs. Remarkably, the IL-17+Treg compartment was preferentially reduced relative to the canonical Th17 and Treg compartments in a subset of HIV+ subjects, suggesting a specific perturbation of this subset during the course of disease. Our findings that CCR6+ naïve precursors contain a predetermined reservoir to replenish IL-17-secreting cells, may have implications in balancing the Th17 and IL-17+Treg compartments that are perturbed during HIV infection and potentially in other inflammatory diseases.

Objectives: We sought to describe the presentation, course, and outcomes of hospitalized pediatric coronavirus disease 2019 patients, with detailed description of those requiring mechanical ventilation, and comparisons between critically ill and noncritical hospitalized pediatric patients. Design: Observational cohort study.