c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis

• Published in: Blood 2006-05, Vol.107 (10), p.3992-3999
• Main Authors: Bianchi, Teresa, Gasser, Stephan, Trumpp, Andreas, MacDonald, H. Robson
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Homeostasis; Hyaluronan Receptors - immunology; Immunobiology; Immunologic Memory; Interleukin-15 - physiology; Lymphocyte Activation; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-myc - deficiency; Proto-Oncogene Proteins c-myc - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-09-3851

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 interleukin-15 (IL-15); however, the downstream signaling pathways regulating IL-15–dependent homeostatic proliferation are poorly defined. Surprisingly, we show here that haploinsufficiency of the protooncogene 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.