Truncated form of TGF-?RII, but not its absence, induces memory CD8+ T cell expansion and lymphoproliferative disorder in mice.

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

SUBMITTER: Ishigame H 

PROVIDER: S-EPMC3690649 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature