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

TitleCD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.
Publication TypeJournal Article
Year of Publication2012
AuthorsKwon DS, Angin M, Hongo TC, Law KM, Johnson J, Porichis F, Hart MG, Pavlik DF, Tighe DP, Kavanagh DG, Streeck H, Addo MM, Kaufmann DE
JournalJ Virol
Volume86
Issue12
Pagination6586-94
Date Published2012 Jun
ISSN1098-5514
KeywordsCD4-Positive T-Lymphocytes, HIV Infections, HIV-1, Humans, Interferon-gamma, Interleukin-10, Interleukin-2 Receptor alpha Subunit, Leukocytes, Mononuclear, Monocytes, T-Lymphocytes, Regulatory, Up-Regulation
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.

DOI10.1128/JVI.06251-11
Alternate JournalJ. Virol.
PubMed ID22496237