An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation.
Rapid proliferation is one of the important features of memory CD8(+) T cells, ensuring rapid clearance of reinfection. Although several cytokines such as IL-15 and IL-7 regulate relatively slow homeostatic proliferation of memory T cells during the maintenance phase, it is unknown how memory T cells can proliferate more quickly than naïve T cells upon antigen stimulation. To examine antigen-specific CD8(+) T cell proliferation in recall responses in vivo, we targeted a model antigen, ovalbumin(OVA), to DEC-205(+) dendritic cells (DCs) with a CD40 maturation stimulus. This led to the induction of functional memory CD8(+) T cells, which showed rapid proliferation and multiple cytokine production (IFN-gamma, IL-2, TNF-alpha) during the secondary challenge to DC-targeted antigen. Upon antigen-presentation, IL-18, an IFN-gamma-inducing factor, accumulated at the DC:T cell synapse. Surprisingly, IFN-gamma receptors were required to augment IL-18 production from DCs. Mice genetically deficient for IL-18 or IFN-gamma-receptor 1 also showed delayed expansion of memory CD8(+) T cells in vivo. These results indicate that a positive regulatory loop involving IFN-gamma and IL-18 signaling contributes to the accelerated memory CD8(+) T cell proliferation during a recall response to antigen presented by DCs.
Laboratory of Cellular Immunology and Physiology, The Rockefeller University, New York, New York, United States of America.
Yoshiko
Y
Iwai
Hiroaki
H
Hemmi
Olga
O
Mizenina
Shoko
S
Kuroda
Koji
K
Suda
Ralph M
RM
Steinman
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000378:metabolism
D015703:Antigens, CD; D019013:CD40 Antigens; D016207:Cytokines; C093569:DEC-205 receptor; D020382:Interleukin-18; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D007371:Interferon-gamma