c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis.
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 CD44(high) 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 CD44(high) CD8 T cells in mice. Although steady-state proliferation and survival of CD44(high) CD8 T cells appeared not to be dependent on c-Myc, homeostatic proliferation of c-myc(+/-) CD44(high) 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(+/-) CD44(high) 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 CD44(high) CD8 T cells decreased in an additive fashion in mice heterozygous for c-myc and IL-15. Finally homeostatic proliferation of antigen-specific memory CD44(high) 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 CD44(high) CD8 T cells.
Bianchi
Teresa
T
Ludwig Institute for Cancer Research (LICR), Ch. des Boveresses 155, 1066 Epalinges, Switzerland.
Gasser
Stephan
S
Trumpp
Andreas
A
MacDonald
H Robson
HR
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006706:Homeostasis; D018960:Hyaluronan Receptors / Q000276:immunology; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000502:physiology*
D018960:Hyaluronan Receptors; D019409:Interleukin-15; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc