Interleukin-2 rescues helpless effector CD8+ T cells by diminishing the susceptibility to TRAIL mediated death

Department of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Immunology letters (Impact Factor: 2.51). 05/2011; 139(1-2):25-32. DOI: 10.1016/j.imlet.2011.04.011
Source: PubMed

ABSTRACT CD8(+) T cells primed in the absence of CD4(+) T cell help are programmed to produce TRAIL, which results in Death receptor (DR5) mediated apoptosis upon restimulation. Here, we studied whether these 'helpless' effector CD8(+) T cells are consigned to an apoptotic fate or whether their helpless program can be altered by inflammatory or growth cytokines. We found that helpless CD8(+) T cells regained their full proliferative and functional capacity only when IL-2 was added to cell cultures, while IL-7 and IL-15, two common gamma chain cytokines associated with CD8(+) T cell homeostasis and memory, could only partly restore secondary expansion in helpless CD8(+) T cells. Recovery of functional CD8(+) T cell immunity by IL-2 was concomitant with induction of IL2Rα (CD25) expression, downregulation of TRAIL, and the upregulation of anti-apoptotic molecules Bcl-2 and FLIP. The addition of IL-2 to helpless CD8(+) T cells also interfered with DR5-mediated apoptosis induction, indicating that IL-2 affects several components of the TRAIL-DR5 pathway. Collectively, these data demonstrate that the helpless phenotype is not fixed, and that IL-2R signaling at the time of reactivation can play an important role in restoring CD8(+) T cell function.

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Available from: Edith M Janssen, Sep 28, 2015
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    • "Importantly, evidence has been provided that IL-12R does not signal through PI3K, and also fails to induce EGR-1 [22] [23]. This is also in line with our previous findings that IL-2 and IL-15 triggering of T cells affects TRAIL expression in murine T cells in a Nab2-dependent manner, while IL-12 triggering fails to do so [24]. Of note, also other early activation gene family members such as c-fos and junB, and the transcription factor AP-1 are induced upon IL-2R signalling, but not upon IL-12R-mediated signalling [23]. "
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    ABSTRACT: The transcriptional regulator NGFI-A binding protein 2 (NAB2) and the early growth response (EGR) genes are key regulators of effector molecules, such as cell death-inducing genes. We have previously shown that NAB2 modulates the levels of expression of the Tumor Necrosis Factor (TNF) family member TNF-related apoptosis inducing ligand (TRAIL) in T cells and plasmacytoid DCs. Provided that TRAIL plays a key role in NK cell cytotoxicity towards infected and tumor cells, we investigated whether NAB2 also mediates TRAIL expression in human NK cells, and if so through which mechanisms. We show that NAB2 is induced in NK cells upon IL-2 and IL-15 stimulation, and promotes the induction of TRAIL. In addition, we show that the transcription factor EGR-1, which is upregulated by the same stimuli as NAB2, rather acts as a brake on TRAIL expression in NK cells. Overall, these data provide new mechanistic insights in the regulation of TRAIL, and show that the gene regulation through the NAB2/EGR axis allows for a highly controlled expression pattern of this effector molecule in NK cells.
    Immunology letters 02/2013; 151(1-2). DOI:10.1016/j.imlet.2013.02.001 · 2.51 Impact Factor
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    ABSTRACT: CD4(+) Th cells are pivotal for the generation and maintenance of CD8(+) T-cell responses. "Helped" CD8(+) T cells receive signals during priming that prevent the induction of the proapoptotic molecule TNF-related apoptosis-inducing ligand (TRAIL) during reactivation, thereby enabling robust secondary expansion. Conversely, "helpless" CD8(+) T cells primed in the absence of Th induce TRAIL expression after restimulation and undergo activation-induced cell death. In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade. Finally, we observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. These findings identify Nab2 as a mediator of Th-dependent CD8(+) T-cell memory responses through the regulation of TRAIL and the promotion of secondary expansion, and suggest a mechanism through which this operates.
    Blood 11/2011; 119(3):798-804. DOI:10.1182/blood-2011-08-373910 · 10.45 Impact Factor
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    ABSTRACT: CD8(+) cytotoxic T lymphocytes are critical components of immunity against infectious pathogens, tumours, and in the case of pathogenic autoimmunity, normal self tissues. CD4(+) T (T(H)) cells provide 'help' to CD8(+) cytotoxic T lymphocytes during priming by first activating antigen-presenting cells via CD40-CD40L interactions. Here we show that, after immunization with either a noninflammatory, nonreplicating antigen or an overtly inflammatory replicating antigen, CD8(+) cytotoxic T lymphocytes prevented from receiving a signal through CD27 during priming subsequently exhibit a specific defect in their capacity for secondary expansion that can be rescued by the absence of TRAIL. Thus, the 'help message' is transmitted to CD8(+) T cells via CD70-CD27 signals, enabling them to undergo secondary expansion and avoid TRAIL-mediated apoptosis on re-stimulation. These findings complete our understanding of the cellular interactions through which T(H) is provided to CD8(+) cytotoxic T lymphocytes during priming.
    Nature Communications 07/2012; 3:948. DOI:10.1038/ncomms1948 · 11.47 Impact Factor
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