Truncated Form of TGF-βRII, But Not Its Absence, Induces Memory CD8+ T Cell Expansion and Lymphoproliferative Disorder in Mice

Inflammatory and anti-inflammatory cytokines play an important role in the generation of effector and memory CD8(+) T cells. We used two different models, transgenic expression of truncated (dominant negative) form of TGF-beta RII (dnTGF beta RII) and Cremediated deletion of the floxed TGF-beta RII to examine the role of TGF-beta signaling in the formation, function, and homeostatic proliferation of memory CD8(+) T cells. Blocking TGF-beta signaling in effector CD8(+) T cells using both of these models demonstrated a role for TGF-beta in regulating the number of short-lived effector cells but did not alter memory CD8(+) T cell formation and their function upon Listeria monocytogenes infection in mice. Interestingly, however, a massive lymphoproliferative disorder and cellular transformation were observed in Ag-experienced and homeostatically generated memory CD8(+) T cells only in cells that express the dnTGF beta RII and not in cells with a complete deletion of TGF-beta RII. Furthermore, the development of transformed memory CD8(+) T cells expressing dnTGF beta RII was IL-7- and IL-15-independent, and MHC class I was not required for their proliferation. We show that transgenic expression of the dnTGF beta RII, rather than the absence of TGF-beta RII-mediated signaling, is responsible for dysregulated expansion of memory CD8(+) T cells. This study uncovers a previously unrecognized dominant function of the dnTGF beta RII in CD8(+) T cell proliferation and cellular transformation, which is caused by a mechanism that is different from the absence of TGF-beta signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF-beta signaling in CD8(+) T cells.