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

Recent evidence showed that transforming growth factor‐β (TGF‐β) regulates the global expansion of CD8+ T cells, which are CD44hi, 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‐β on antigen‐specific CD8+ memory cells [cytotoxic T lymphocyte (CTL)]. We found that the secondary CTL response in CD8+ memory cells from untreated MLC was not affected by TGF‐β but augmented by interleukin (IL)‐2, whereas the CD8+ memory cells from TGF‐β‐pretreated MLC (MLC‐TGF‐β) failed to mount a significant, secondary CTL response, even when IL‐2 was added. In exploring this dichotomy, in combination with flow cytometry analysis, we found that prolonged exposure to TGF‐β reduces the CTL activity in CD8+ memory cells. The increase by IL‐2 and the reduction by TGF‐β of the CTL responses were clonal‐specific. TGF‐β did not affect the CTL response to a third‐party antigen or polyclonal T cell activation. Experiments performed with transgenic 2C cells gave similar results. Cell‐cycle study performed with adoptive transfer of the cell tracker‐labeled MLC cells revealed that the in vivo expansion of CD8+ memory cells from MLC‐TGF‐β was restricted severely, and the restriction was clonal‐specific, thus offering direct evidence to show that TGF‐β induces clonal restriction of CD8+ memory cell expansion.