title: Nab2 regulates secondary CD8+ T-cell responses through control of TRAIL expression.
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.
authors: Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, CA, USA. m.wolkers@sanquin.nl
authors: Monika C
authors: MC
authors: Wolkers
authors: Carmen
authors: C
authors: Gerlach
authors: Ramon
authors: R
authors: Arens
authors: Edith M
authors: EM
authors: Janssen
authors: Patrick
authors: P
authors: Fitzgerald
authors: Ton N
authors: TN
authors: Schumacher
authors: Jan Paul
authors: JP
authors: Medema
authors: Douglas R
authors: DR
authors: Green
authors: Stephen P
authors: SP
authors: Schoenberger
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D007376:Interleukin-2; D009124:Muscle Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C035620:nebulin