Submitted May 25, 2006
Accepted June 11, 2006
Dysregulation of IL-15-mediated T cell homeostasis in
TGF-
dominant negative receptor transgenic mice
Philip J Lucas*, Seong-Jin Kim, Crystal L Mackall, William G Telford, Yu-Waye Chu, Frances T Hakim, and Ronald E Gress
Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD,USA
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD, USA
Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
* Corresponding author; email: pjlucas{at}nih.gov.
T-cell subpopulations, defined by their expression of CD4,
CD8, naive, and memory cell surface markers, occupy
distinct homeostatic compartments that are regulated
primarily by cytokines. CD8+ memory T cells, as
defined by CD44hi surface expression, are
dependent on IL-15 as a positive regulator in their
homeostatic maintenance. Manipulation of IL-15 signaling
through gene aberration, over-expression, or receptor
alterations, has been shown to dramatically affect T cell
homeostasis, with over-expression leading to fatal
leukemia. Here we show that TGF-
is the critical
negative regulator of murine CD8+ memory T cell
homeostasis with direct opposition to the positive effects
of IL-15. This negative regulation is mediated, at least
in part, by the ability of TGF- to modulate
expression of the beta chain of the IL-15 receptor, thus
establishing a central axis between these two cytokines
for homeostatic control of CD8+ memory T cell
populations. These data establish TGF- as a
critical and dominant tumor suppressor pathway opposing
IL-15 mediated CD8+ T-cell expansion and
potential malignant transformation.
