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

Abstract

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.