IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Cha, Lilian; Jong, Emma de; French, Martyn A.; Fernández, Sonia

doi:10.4049/jimmunol.1302536

Cited by 21 publications

(21 citation statements)

References 52 publications

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“…As the CD25 gene promoter region has a well-defined STAT5 binding site, which promotes transcriptional activation [33,34], this observation suggests that P-STAT5 signaling is not impaired downstream of phosphorylation when cells are treated with IFN-a, at least at the time-point and under the conditions used here. The sustained capacity of cells to signal via P-STAT5 in the presence of IFN-a, despite reductions in P-AKT signaling, is also consistent with reports by others that IFN-a impairs IL-7-induced T cell proliferation but does not inhibit P-STAT5 signaling in primary T cells [35].…”

Section: Discussionsupporting

confidence: 90%

“…For the latter possibility, we found no evidence, at least for CD127, that cytokine receptor expression was disrupted by IFN-a (not shown). Recent studies by others also indicate that IFN-a does not impair CD127 expression in T cells and may actually enhance expression in long-term cultures [35]. The delay in P-Akt that occurs after IL-7 stimulation is consistent with the possibility that IL-7 may induce a secondary factor that leads to enhancement of the signal.…”

Section: Discussionsupporting

confidence: 58%

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Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling

Nguyen

Bazdar

Mudd

et al. 2015

Journal of Leukocyte Biology

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Persistent type I IFN production occurs during chronic viral infections, such as HIV disease. As type I IFNs have antiproliferative activity, it is possible that chronic exposure to these cytokines could adversely affect T cell homeostasis. We investigated the capacity of IFN-α to impair T cell proliferation induced by the homeostatic cytokine, IL-7, or another common γ-chain cytokine, IL-2, in cells from healthy human donors. We found that IL-7- or IL-2-induced proliferation of CD4(+) T cells was partially inhibited in the presence of IFN-α. The CD4(+) T cells that were exposed to IFN-α also displayed attenuated induction of IL-2 and CD40L following TCR stimulation. Analyses of signaling pathways indicated that IL-7 and IL-2 induced a delayed and sustained P-Akt signal that lasted for several days and was partially inhibited by IFN-α. In contrast, IL-7-induced P-STAT5 was not affected by IFN-α. Furthermore, IFN-α had no detectable effect on P-Akt that was induced by the chemokine SDF-1. Both inhibitors of P-Akt and P-STAT5 blocked IL-7-induced T cell proliferation, confirming that both signaling pathways are important for IL-7-induced T cell proliferation. These results demonstrate that IFN-α can selectively inhibit cytokine-induced P-Akt as a potential mechanism to disrupt homeostasis of T lymphocytes.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 58%

Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling

Nguyen

Bazdar

Mudd

et al. 2015

Journal of Leukocyte Biology

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“…Both of these effects may adversely affect CD4 + T-cell homoeostasis in HIV patients, promoting the loss of T cells by accelerating cell turnover and activation-induced cell death, and decreasing the renewal of T cells by inhibiting the proliferative effects of IL-7. 39 …”

Section: Ifn-α and Immune Dysfunction In Hiv And Siv Infectionmentioning

confidence: 99%

Interferon‐alpha, immune activation and immune dysfunction in treated HIV infection

et al. 2014

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Type I interferons (IFNs) exert anti-viral effects through the induction of numerous IFN-stimulated genes and an immunomodulatory effect on innate and adaptive immune responses. This is beneficial in controlling virus infections but prolonged IFN-α activity in persistent virus infections, such as HIV infection, may contribute to immune activation and have a detrimental effect on the function of monocytes and T and B lymphocytes. Activation of monocytes, associated with increased IFN-α activity, contributes to atherosclerotic vascular disease, brain disease and other ‘age-related diseases' in HIV patients treated with long-term antiretroviral therapy (ART). In HIV patients receiving ART, the anti-viral effects of IFN-α therapy have the potential to contribute to eradication of HIV infection while IFN-α inhibitor therapy is under investigation for the treatment of immune activation. The management of HIV patients receiving ART will be improved by understanding more about the opposing effects of IFN-α on HIV infection and disease and by developing methods to assess IFN-α activity in clinical practice.

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“…High IL-7 plasma levels as well as decreased membrane-associated (m)IL-7R expression of T cells were found in AIDS patients with immune failure [16, 17]. Concomitantly impaired T-cell response to IL-7 was detected in immune failure patients [13–15, 18–20]. …”

Section: Introductionmentioning

confidence: 99%

Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis

et al. 2017

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T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We performed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/sIL-7R and mIL-7R expression, respectively. IL-7-dependent T-cell functions were determined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by analysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normalised during therapy and recovery. Furthermore, tuberculosis patients had lower levels of mIL-7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indicated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted cytokine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T-cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients.

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IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Cited by 21 publications

References 52 publications

Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling

Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling

Interferon‐alpha, immune activation and immune dysfunction in treated HIV infection

Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis

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