an ifn-γ-il-18 signaling loop accelerates memory cd8+ t cell proliferation一个ifn-γ-il-18信号循环加速记忆的cd8 + t细胞增殖.pdfVIP

An IFN-c-IL-18 Signaling Loop Accelerates Memory CD8+ T Cell Proliferation 1,2 1,2 1 2 1 1 Yoshiko Iwai , Hiroaki Hemmi , Olga Mizenina , Shoko Kuroda , Koji Suda , Ralph M. Steinman * 1 Laboratory of Cellular Immunology and Physiology, The Rockefeller University, New York, New York, United States of America, 2 Medical Top Track (MTT) Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan Abstract 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 naıve 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-c, IL-2, TNF-a) during the secondary challenge to DC-targeted antigen. Upon antigen-presentation, IL-18, an IFN-c-inducing factor, accumulated at the DC:T cell synapse. Surprisingly, IFN-c receptors were required to augment IL-18 production from DCs. Mice genetically deficient for IL-18 or IFN-c-receptor 1 also showed delayed expansion of memory CD8+ T cells in vivo. These results indicate that a positive regulatory loop involving IF