IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival.
Natural killer T (NKT) cells are innate-like T cells that rapidly recognize pathogens and produce cytokines that shape the ensuing immune response. IL-17-producing NKT cells are enriched in barrier tissues, such as the lung, skin, and peripheral lymph nodes, and the factors that maintain this population in the periphery have not been elucidated. Here we show that NKT17 cells deviate from other NKT cells in their survival requirements. In contrast to conventional NKT cells that are maintained by IL-15, RORγt(+) NKT cells are IL-15 independent and instead rely completely on IL-7. IL-7 initiates a T-cell receptor-independent (TCR-independent) expansion of NKT17 cells, thus supporting their homeostasis. Without IL-7, survival is dramatically impaired, yet residual cells remain lineage committed with no downregulation of RORγt evident. Their preferential response to IL-7 does not reflect enhanced signaling through STAT proteins, but instead is modulated via the PI3K/AKT/mTOR signaling pathway. The ability to compete for IL-7 is dependent on high-density IL-7 receptor expression, which would promote uptake of low levels of IL-7 produced in the non-lymphoid sites of lung and skin. This dependence on IL-7 is also reported for RORγt(+) innate lymphoid cells and CD4(+) Th17 cells, and suggests common survival requirements for functionally similar cells.
1] Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
K E
KE
Webster
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
H-O
HO
Kim
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.
K
K
Kyparissoudis
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
T M
TM
Corpuz
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
G V
GV
Pinget
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.
A P
AP
Uldrich
1] Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
R
R
Brink
1] Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Australia.
G T
GT
Belz
1] Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
J-H
JH
Cho
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.
D I
DI
Godfrey
1] Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia [2] St Vincent's Clinical School, University of New South Wales, Sydney, Australia [3] Academy of Immunology and Microbiology, Institute for Basic Science, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
J
J
Sprent
D000818:Animals; D049109:Cell Proliferation; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
D020381:Interleukin-17; D015851:Interleukin-7