Nab2 regulates secondary CD8+ T-cell responses through control of TRAIL expression

Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, CA, USA.
Blood (Impact Factor: 10.45). 11/2011; 119(3):798-804. DOI: 10.1182/blood-2011-08-373910
Source: PubMed


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.

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Available from: Stephen P. Schoenberger
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    • "To assess whether the transcriptional regulator NAB2 mediates the expression of TRAIL in NK cells, comparable to what is found in T cells and pDCs [4] [5], we first determined if NAB2 expression was induced by two key mediators of NK cell activation and cytotoxicity , IL-2 and IL-15 [9,17]. We found that in primary human NK cells the expression of NAB2 mRNA upon overnight stimulation with IL-2 and IL-15 was increased by a two-three fold compared to unstimulated NK cells (Fig. 1A, p = 0.0035, p = 0.001). "
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