title: CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.
abstract: 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.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Charlestown, Massachusetts, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kwon
authors.forename: Mathieu
authors.initials: M
authors.lastname: Angin
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hongo
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Law
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
authors.forename: Meghan G
authors.initials: MG
authors.lastname: Hart
authors.forename: David F
authors.initials: DF
authors.lastname: Pavlik
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Tighe
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kavanagh
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma