TGF-β Sensitivity Restrains CD8+T Cell Homeostatic Proliferation by Enforcing Sensitivity to IL-7 and IL-15

The pleiotropic cytokine TGF-beta has been implicated in the regulation of numerous aspects of the immune response, including naive T cell homeostasis. Previous studies found that impairing TGF-beta responsiveness (through expression of a dominant-negative TGF-beta RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity. Here we show naive DNRII CD8 T cells exhibit enhanced lymphopenia-driven proliferation and generation of "homeostatic'' memory cells. However, this enhanced response occurred in the absence of IL-15 and, unexpectedly, even in the combined absence of IL-7 and IL-15, which were thought essential for CD8 T cell homeostatic expansion. DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues. These findings suggest TGF-beta responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).