Dysregulation of IL-15-mediated T-cell homeostasis in TGF-β dominant-negative receptor transgenic mice

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 CD44^hi surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-β 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-β to modulate expression of the β-chain of the IL-15 receptor, thus establishing a central axis between these 2 cytokines for homeostatic control of CD8⁺ memory T-cell populations. These data establish TGF-β as a critical and dominant tumor-suppressor pathway opposing IL-15-mediated CD8⁺ T-cell expansion and potential malignant transformation.