Evidence of a novel IL-2/15R beta-targeted cytokine involved in homeostatic proliferation of memory CD8+ T cells.
The homeostasis of memory CD8+ T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of memory CD8+ T cells, while IL-2 suppresses their division in vivo. This inhibitory effect of IL-2 appears to occur indirectly, through other cell populations including CD25+CD4+ T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8+ T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44(high)IL-2/15Rbeta(high) CD8+ T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rbeta signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8+ T cells, although the only cytokines known to act through IL-2/15Rbeta are IL-2 and IL-15; and 4) the expression of IL-2/15Rbeta molecules on memory CD8+ T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8+ T cell division by an IL-15-independent but by an IL-2/15Rbeta-dependent mechanism, suggesting the existence of a novel IL-2/15Rbeta-utilizing cytokine that acts directly on memory CD8+ T cells to promote cell division.
Kamimura
Daisuke
D
Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Ueda
Naoko
N
Sawa
Yukihisa
Y
Hachida
Shinji
S
Atsumi
Toru
T
Nakagawa
Takayuki
T
Sawa
Shin-ichiro
S
Jin
Gui-Hua
GH
Suzuki
Haruhiko
H
Ishihara
Katsuhiko
K
Murakami
Masaaki
M
Hirano
Toshio
T
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053646:Interleukin-2 Receptor beta Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000276:immunology; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D018960:Hyaluronan Receptors; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2