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. 2014 Aug 15;210(4):619-29.
doi: 10.1093/infdis/jiu125. Epub 2014 Feb 28.

Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease

Carey L Shive  1 , Joseph C Mudd  1 , Nicholas T Funderburg  2 , Scott F Sieg  1 , Benjamin Kyi  1 , Doug A Bazdar  1 , Davide Mangioni  3 , Andrea Gori  3 , Jeffrey M Jacobson  4 , Ari D Brooks  5 , Jeffrey Hardacre  6 , John Ammori  6 , Jacob D Estes  7 , Timothy W Schacker  8 , Benigno Rodriguez  1 , Michael M Lederman  1
Affiliations

Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease

Carey L Shive et al. J Infect Dis. .

Abstract

Background: Systemic inflammation has been linked to a failure to normalize CD4(+) T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure.

Methods: We examined the in vitro effects of IL-6 and interleukin 1β (IL-1β) on peripheral blood T-cell cycling and CD127 surface expression.

Results: The proinflammatory cytokine IL-1β induces cell cycling and turnover of memory CD4(+) T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1β and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor α chain (IL-7Rα). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1β attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin α4β7. We found elevated expression of IL-1β in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy.

Conclusions: Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects.

Keywords: HIV; immune failure; inflammation; interleukin 1 beta; interleukin 6; interleukin 7.

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Figures

Figure 1.
Figure 1.
Interleukin 6 (IL-6) and interleukin 1β (IL-1β) induce cell cycle initiation in T cells. A, Peripheral blood mononuclear cells from a healthy subject were stimulated with IL-6 (10 ng/mL), IL-1β (10 ng/mL), or interleukin 7 (IL-7; 2 ng/mL) for 7 days. After 7 days, cells were washed, stained for intranuclear Ki67, and examined by flow cytometry. B, Summary data of Ki67 induction by IL-6 (n = 10) and IL-1β (n = 11). Group data were compared using the Mann–Whitney U test. C, IL-1β–induced cycling is highest in memory T cells; IL-6-induces cycling in naive T cells. Central memory, CD45RA−CCR7+CD27+; effector memory, CD45RA−CCR7−CD27−; naive, CD45RA+CCR7+CD27+.
Figure 2.
Figure 2.
Inflammatory cytokines drive cell proliferation. A, Peripheral blood mononuclear cells from a healthy control were stained with CFSE dye and cultured for 7 days with interleukin 6 (IL-6; 10 ng/mL), interleukin 1β (IL-1β; 10 ng/mL), or interleukin 7 (IL-7; 2 ng/mL). After 7 days, cells were washed, stained for surface markers, and acquired by flow cytometry. B, Summary data of 3 experiments. C, Proliferation of CD4+ T-cell maturation subsets. IL-7–induced proliferation is seen in all CD4+ T-cell maturation subsets, whereas IL-1β–induced proliferation is seen almost exclusively in memory T cells. Data shown are representative of 6 experiments, using 4 different subjects. D, Proliferation of CD8+ T-cell maturation subsets. Data shown are representative of 6 experiments, using 4 different subjects. Maturation subsets were determined as outlined in Figure 1.
Figure 2.
Figure 2.
Inflammatory cytokines drive cell proliferation. A, Peripheral blood mononuclear cells from a healthy control were stained with CFSE dye and cultured for 7 days with interleukin 6 (IL-6; 10 ng/mL), interleukin 1β (IL-1β; 10 ng/mL), or interleukin 7 (IL-7; 2 ng/mL). After 7 days, cells were washed, stained for surface markers, and acquired by flow cytometry. B, Summary data of 3 experiments. C, Proliferation of CD4+ T-cell maturation subsets. IL-7–induced proliferation is seen in all CD4+ T-cell maturation subsets, whereas IL-1β–induced proliferation is seen almost exclusively in memory T cells. Data shown are representative of 6 experiments, using 4 different subjects. D, Proliferation of CD8+ T-cell maturation subsets. Data shown are representative of 6 experiments, using 4 different subjects. Maturation subsets were determined as outlined in Figure 1.
Figure 3.
Figure 3.
Interleukin 6 (IL-6) and interleukin 1β (IL-1β) downregulate CD127 surface expression on CD4+ T cells. Representative and summaries of CD127 surface expression assessed on CD4+ and CD8+ T cells in peripheral blood mononuclear cells (PBMCs) treated for 2 days in the presence or absence of 1 ng/mL IL-6 (A) or 10 ng/mL IL-1β (B). Representative and summaries of CD127 surface expression in CD4+ T-cell subsets assessed in PBMCs treated in the presence or absence of 1 ng/mL IL-6 (C) or 10 ng/mL of IL-1β (D) for 2 days. E, CD127 messenger RNA expression normalized to 18S ribosomal RNA, as assessed by real-time polymerase chain reaction analysis, in naive CD4+ T cells separated from PBMCs treated for 2 days with or without IL-6 or IL-1β. Data shown represent means and SD of 3 experiments. Statistical comparisons were performed using the Wilcoxon signed rank test.
Figure 4.
Figure 4.
Interleukin 6 (IL-6) and interleukin 1β (IL-1β) impair T-cell responses to interleukin 7 (IL-7). Peripheral blood mononuclear cells (PBMCs) from a healthy donor were treated in medium alone or supplemented with 1 ng/mL IL-6 or 10 ng/mL IL-1β for 2 days, followed by addition of 5 ng/mL IL-7. A, Stat-5 phosphorylation was measured 5 days after IL-7 addition. Representative and summary of 7 independent experiments are shown as means and standard errors. B, Surface staining for the α4β7 heterodimer 5 days after IL-7 addition. C, PBMCs from healthy donors were treated in medium alone or supplemented with 10 ng/mL IL-6 or 10 ng/mL IL-1β for 2 days, and intracellular Bcl2 expression was measured in CD4+ and CD8+ T cells 7 days after addition of IL-7 (2 ng/mL).
Figure 5.
Figure 5.
Interleukin 1β (IL-1β) is expressed in lymph nodes from human immunodeficiency virus (HIV)–infected patients and is decreased but not normalized in patients who received antiretroviral therapy (ART). A, Mature IL-1β stained lymph node (LN) sections from 2 healthy controls, 2 viremic HIV-positive patients, and 2 HIV-positive patients receiving ART (100× original magnification; insets, 200×). B, Summary data of LN IL-1β staining from 6 healthy controls, 5 untreated HIV-infected viremic patients, and 8 HIV-positive ART-treated patients.
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