CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.
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CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes. / Kwon, Douglas S; Angin, Mathieu; Hongo, Tomoyuki; Law, Kenneth M; Johnson, Jessica; Porichis, Filippos; Hart, Meghan G; Pavlik, David F; Tighe, Daniel P; Kavanagh, Daniel G; Streeck, Hendrik; Addo, Marylyn; Kaufmann, Daniel E.
In: J VIROL, Vol. 86, No. 12, 12, 2012, p. 6586-6594.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.
AU - Kwon, Douglas S
AU - Angin, Mathieu
AU - Hongo, Tomoyuki
AU - Law, Kenneth M
AU - Johnson, Jessica
AU - Porichis, Filippos
AU - Hart, Meghan G
AU - Pavlik, David F
AU - Tighe, Daniel P
AU - Kavanagh, Daniel G
AU - Streeck, Hendrik
AU - Addo, Marylyn
AU - Kaufmann, Daniel E
PY - 2012
Y1 - 2012
N2 - 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-?) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-? 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-?), 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.
AB - 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-?) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-? 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-?), 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.
KW - Humans
KW - T-Lymphocytes, Regulatory/immunology
KW - Interferon-gamma/immunology
KW - Leukocytes, Mononuclear/immunology
KW - Up-Regulation
KW - CD4-Positive T-Lymphocytes/immunology
KW - HIV Infections/immunology/virology
KW - HIV-1/immunology/physiology
KW - Interleukin-10/blood/immunology
KW - Interleukin-2 Receptor alpha Subunit/immunology
KW - Monocytes/immunology
KW - Humans
KW - T-Lymphocytes, Regulatory/immunology
KW - Interferon-gamma/immunology
KW - Leukocytes, Mononuclear/immunology
KW - Up-Regulation
KW - CD4-Positive T-Lymphocytes/immunology
KW - HIV Infections/immunology/virology
KW - HIV-1/immunology/physiology
KW - Interleukin-10/blood/immunology
KW - Interleukin-2 Receptor alpha Subunit/immunology
KW - Monocytes/immunology
M3 - SCORING: Journal article
VL - 86
SP - 6586
EP - 6594
JO - J VIROL
JF - J VIROL
SN - 0022-538X
IS - 12
M1 - 12
ER -
