Truncated form of TGF-ßRII, 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-ßRII (dnTGFßRII) and Cre-mediated deletion of the floxed TGF-ßRII to examine the role of TGF-ß signaling in the formation, function, and homeostatic proliferation of memory CD8(+) T cells. Blocking TGF-ß signaling in effector CD8(+) T cells using both of these models demonstrated a role for TGF-ß 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 dnTGFßRII and not in cells with a complete deletion of TGF-ßRII. Furthermore, the development of transformed memory CD8(+) T cells expressing dnTGFßRII was IL-7- and IL-15-independent, and MHC class I was not required for their proliferation. We show that transgenic expression of the dnTGFßRII, rather than the absence of TGF-ßRII-mediated signaling, is responsible for dysregulated expansion of memory CD8(+) T cells. This study uncovers a previously unrecognized dominant function of the dnTGFßRII in CD8(+) T cell proliferation and cellular transformation, which is caused by a mechanism that is different from the absence of TGF-ß signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF-ß signaling in CD8(+) T cells.