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Blood, 15 May 2006, Vol. 107, No. 10, pp. 3992-3999.
Prepublished online as a Blood First Edition Paper on January 31, 2006; DOI 10.1182/blood-2005-09-3851.
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Submitted September 28, 2005
Accepted January 16, 2006
c-Myc acts downstream of IL-15 in the regulation of memory CD8 T cell homeostasis
Teresa Bianchi, Stephan Gasser, Andreas Trumpp, and H. Robson MacDonald*
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland
Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research and Swiss Institute of Technology Lausanne, Epalinges, Switzerland
* Corresponding author; email: HughRobson.MacDonald{at}isrec.unil.ch.
A subset of CD8 T cells in normal mice, expressing high levels of activation markers such as CD44, shares many properties with antigen-specific memory CD8 T cells. Homeostasis of CD44high CD8 T cells depends upon cytokines such as IL-15; however, the downstream signaling pathways regulating IL-15-dependent homeostatic proliferation are poorly defined. Surprisingly, we show here that haploinsufficiency of the proto-oncogene c-myc leads to a highly selective decrease in CD44high CD8 T cells in mice. Although steady-state proliferation and survival of CD44high CD8 T cells appeared not to be dependent on c-Myc, homeostatic proliferation of c-myc+/- CD44high CD8 T cells in lymphopenic hosts was strongly reduced and the residual homeostatic proliferation of these cells appeared to occur independently of IL-15. Moreover, c-myc+/- CD44high CD8 T cells responded very poorly to purified IL-15 in vitro. Backcrossing of c-myc+/- mice to IL-15-/- mice revealed that the number of CD44high CD8 T cells decreased in an additive fashion in mice heterozygous for c-myc and IL-15. Finally homeostatic proliferation of antigen-specific memory CD44high CD8 T cells was also impaired in c-myc+/- mice. Collectively, our data identify c-Myc as a novel downstream component of the IL-15-dependent pathway controlling homeostatic proliferation of memory CD44high CD8 T cells.
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