Truncated Form of TGF-bRII, 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-bRII (dnTGFbRII) and Cre-mediated deletion of the floxed TGF-bRII to examine the role of TGF-b signaling in the formation, function, and homeostatic proliferation of memory CD8 + T cells. Blocking TGF-b signaling in effector CD8 + T cells using both of these models demonstrated a role for TGF-b 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 dnTGFbRII and not in cells with a complete deletion of TGF-bRII. Furthermore, the development of transformed memory CD8 + T cells expressing dnTGFbRII was IL-7– and IL-15–independent, and MHC class I was not required for their proliferation. We show that transgenic expression of the dnTGFbRII, rather than the absence of TGF-bRII–mediated signaling, is responsible for dysregulated expansion of memory CD8 + T cells. This study uncovers a previously unrecognized dominant function of the dnTGFbRII in CD8 + T cell proliferation and cellular transformation, which is caused by a mechanism that is different from the absence of TGF-b signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF-b signaling in CD8 + T cells. T he formation of immunological memory begins as naive T cells come in contact with their cognate Ag on activated APCs, undergo clonal expansion, and differentiate into effector T cells, most of which soon die by apoptosis during the " contraction " phase (1–4). During clonal expansion in response to most viral and bacterial infections, multiple subpopulations of effector CD8 + T cells exist, whose survival is regulated by inflammatory and anti-inflammatory cytokines. The subset that survives and becomes memory cells is referred to as memory precursor effector cells (MPECs), which are enriched in CD127 (IL-7Ra) hi KLRG1 lo populations (1, 4). The fraction that dies during contraction is referred to as short-lived effector cells (SLECs), which are enriched in IL-7Ra lo KLRG1 hi populations. Although both subsets have similar functional abilities at the peak of the immune response, they differ greatly in …