CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.

T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-γ) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-γ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.

Ets-1 maintains IL-7 receptor expression in peripheral T cells.

The expression of CD127, the IL-7-binding subunit of the IL-7 R, is tightly regulated during the development and activation of T cells and is reduced during chronic viral infection. However, the molecular mechanism regulating the dynamic expression of CD127 is still poorly understood. In this study, we report that the transcription factor Ets-1 is required for maintaining the expression of CD127 in murine peripheral T cells. Ets-1 binds to and activates the CD127 promoter, and its absence leads to reduced CD127 expression, attenuated IL-7 signaling, and impaired IL-7-dependent homeostatic proliferation of T cells. The expression of CD127 and Ets-1 is strongly correlated in human T cells. Both CD127 and Ets-1 expression are decreased in CD8(+) T cells during HIV infection. In addition, HIV-associated loss of CD127 is only observed in Ets-1(low) effector memory and central memory but not in Ets-1(high) naive CD8(+) T cells. Taken together, our data identify Ets-1 as a critical regulator of CD127 expression in T cells.

Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue.

Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1-infected individuals and HIV-1 negative controls. While HIV "elite controllers" and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors.

Fluid Movement in the Apical Area Beyond the Ledge During Er:YAG Laser-Activated Irrigation: A Particle Image Velocimetry Analysis.

Objective: This study aimed to examine the irrigant flow generated by laser-activated irrigation (LAI), in comparison with ultrasonic-activated irrigation (UAI) and syringe irrigation (SI), in the area beyond the ledge using particle image velocimetry (PIV). Background data: There was no reported study about cleaning efficacy of LAI beyond the ledge. Materials and methods: Forty-nine J-shaped root canal models (40° curvature) were instrumented to no. 35/0.06, and a ledge, 2.5 mm deep, was created with no. 60/0.08 instrument at 5 mm from the apical foramen in each canal. The samples were irrigated with LAI [30 mJ/5 pulse per second (pps), 30 mJ/10 pps, 30 mJ/20 pps, 50 mJ/10 pps, 70 mJ/10 pps], UAI, and SI with a tip/needle insertion depth of 5 mm from the apical foramen (n = 7). PIV was performed with glass beads and a high-speed camera. Velocities were compared in the coronal and apical areas to the ledge, respectively. Results: In the apical area, all LAI groups and UAI produced a higher velocity than that of SI, and LAI at 30 mJ/20 pps and 70 mJ/10 pps showed significantly higher velocity than that of UAI (p < 0.05). In the coronal area, LAI at 30 mJ/20 pps generated a significantly higher velocity than that of UAI and SI (p < 0.05). Velocity was significantly slower in the apical area than in the coronal area in UAI and SI (p < 0.05), but was similar between both areas in LAI except at 30 mJ/20 pps. Conclusions: Among tested laser settings, higher velocity was significantly achieved by LAI at 30 mJ/20 pps and 70 mJ/10 pps compared with UAI in the canal area beyond the ledge. SI generated lower fluid movement than LAI and UAI in both canal regions.

Effect of Pulse Energy, Pulse Frequency, and Tip Diameter on Intracanal Vaporized Bubble Kinetics and Apical Pressure During Laser-Activated Irrigation Using Er:YAG Laser.

Objective: Er:YAG laser-activated irrigation (LAI) is an effective method of root canal cleaning, but irrigant extrusion from the apical foramen has been a concern. We aimed to analyze the effects of pulse energy, pulse frequency, and laser tip diameter on intracanal vapor bubble kinetics and periapical pressure generation during LAI with Er:YAG laser. Background: Irrigant vapor bubble kinetics are one of indices of root canal cleaning efficacy. However, few studies have compared laser pulse conditions to vapor bubble kinetics, in relation to periapical pressure. Methods: A plastic root canal model (apical diameter 0.50 mm, 6% taper, 20 mm long) was filled with distilled water, and LAI with Er:YAG laser (Erwin AdvErl Unit; 30, 50, or 70 mJ; 10, or 20 pulses per second; laser tip R200T or R600T) was performed with the end of the tip fixed at 15 mm from the root apex. The number, maximum diameter, and velocity of vapor bubbles were analyzed by high-speed video imaging. Pressure generated outside the apical foramen was measured with a pressure sensor. Results: Vapor bubble count and maximum diameter increased significantly with pulse energy, pulse frequency, and tip diameter. Vapor bubble velocity increased significantly with pulse frequency, but not with pulse energy or tip diameter. Periapical pressure increased significantly with pulse energy, pulse frequency, and tip diameter. Conclusions: The pulse frequency was the single factor that significantly affected all the examined parameters (the number, diameter, and velocity) of vapor bubble kinetics together with the periapical pressure.