TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15.
In this study, a critical and novel role for TNF receptor (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(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) 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(+) CD44(hi) 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(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) 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(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15.
Transplantation Immunology Group.
Jeanette E
JE
Villanueva
Transplantation Immunology Group.
Elisabeth K
EK
Malle
B cell Biology Group, Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
Sandra
S
Gardam
ANZAC Research Institute, Concord, Australia.
Pablo A
PA
Silveira
Transplantation Immunology Group.
Nathan W
NW
Zammit
Transplantation Immunology Group.
Stacey N
SN
Walters
B cell Biology Group, Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
Robert
R
Brink
Transplantation Immunology Group.
Shane T
ST
Grey
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D060833:Cellular Microenvironment; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006706:Homeostasis; D007156:Immunologic Memory; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000494:pharmacology*; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics* / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D019409:Interleukin-15; D016328:NF-kappa B; D053647:Receptors, Interleukin-15; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D051057:Proto-Oncogene Proteins c-akt
CD8+ T cell; Homeostasis; IL-15; NKT cell; TRAF2; TRAF3