128 : Truncated form of transforming growth factor-β receptor II, but not its absence, induces memory CD8+ T cell expansion and lymphoproliferative disorder in mice

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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 transforming growth factor- β receptor II (dnTGF β RII) and Cre-mediated deletion of the floxed TGF β RII to examine the role of TGF- β signaling in the formation, function, and homeostatic proliferation of memory CD8 + T cells. Blocking TGF- β signaling in effector CD8 + T cells using both of these models demonstrated a role for TGF- β 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 antigen-experienced and homeostatically generated memory CD8 + T cells only in cells that express the dnTGF β RII, but not in cells with a complete deletion of TGF β RII. Furthermore, the development of transformed memory CD8 + T cells expressing dnTGF β 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 β RII, rather than the absence of TGF β RII-mediated signaling, is responsible for dysregulated expansion of memory CD8 + T cells. This study uncovers a previously unrecognized dominant function of the dnTGF β RII in CD8 + T cell proliferation and cellular transformation, which is caused by a mechanism that is different than the absence of TGF- β signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF- β signaling in CD8 + T cells.