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TRAF2 regulates peripheral CD8+ T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15

Abstract

In this study, a critical and novel role for TNFR-associated factor 2 (TRAF2) is elucidated for peripheral CD8+ T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector-memory and ∼50% reduction in naïve CD8+ T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central-memory CD8+ CD44hi CD122+ T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8+ CD44hi T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8+ T cells proliferated normally to anti-CD3 and TRAF2TKO CD8+ CD44hi T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8+ T cells expressed normal levels of IL-15 associated receptors and possessed functional IL-15 mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8+ CD44hi CD122+ and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8+ CD44hi CD122+ T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8+ CD44hi CD122+ T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15 This article is protected by copyright. All rights reserved

Type Journal
Authors Villanueva, J.E.; Malle, E.K.; Gardam, S.; Silveira, P.A.; Zammit, N.W.; Walters, S.N.; Brink, R.; Grey S.T.
Responsible Garvan Author
Publisher Name EUROPEAN JOURNAL OF IMMUNOLOGY
Published Date 2015-06-01
Published Volume 45
Published Issue 6
Published Pages 1820-31
Status Published in-print
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/12769