Clonal restriction of the expansion of antigen-specific CD8+ memory T cells by transforming growth factor-β

Recent evidence showed that trans- forming growth factor- (TGF-) regulates the global expansion of CD8 T cells, which are CD44 hi , a marker for memory cells. However, it is not clear whether this regulatory mechanism also applies to the antigen-specific CD8 memory cells. By using a murine mixed lymphocyte culture (MLC) model, we examined the effect of TGF- on antigen-specific CD8 memory cells (cytotoxic T lymphocyte (CTL)). We found that the secondary CTL response in CD8 memory cells from un- treated MLC was not affected by TGF- but aug- mented by interleukin (IL)-2, whereas the CD8 memory cells from TGF--pretreated MLC (MLC- TGF-) failed to mount a significant, secondary CTL response, even when IL-2 was added. In ex- ploring this dichotomy, in combination with flow cytometry analysis, we found that prolonged expo- sure to TGF- reduces the CTL activity in CD8 memory cells. The increase by IL-2 and the reduc- tion by TGF- of the CTL responses were clonal- specific. TGF- did not affect the CTL response to a third-party antigen or polyclonal T cell activa- tion. Experiments performed with transgenic 2C cells gave similar results. Cell-cycle study per- formed with adoptive transfer of the cell tracker- labeled MLC cells revealed that the in vivo expan- sion of CD8 memory cells from MLC-TGF- was restricted severely, and the restriction was clonal- specific, thus offering direct evidence to show that TGF- induces clonal restriction of CD8 memory cell expansion. J. Leukoc. Biol. 79: 1033-1042; 2006.