CD8⁺ cytotoxic T cell repertoire implicated in graft-versus-leukemia effect in a murine bone marrow transplantation model

Abstract

In our model of murine BMT, the lethal GVHD which develops against DBA/2 host incompatible minor histocompatibility antigens (mHAgs) can be prevented by donor preimmunization before grafting. Recipient mice become long survivors (LS mice) and tolerant to host mHAgs. However, a GVL effect is preserved and mediated by CD8⁺ CTL able to kill P815 tumor cells in vitro and in vivo. To explain why a GVL exists without GVHD, we compared the CTL activity of LS and B10.D2 donor mice after immunization with DBA/2 spleen cells or with P815 cells. Experimental results indicated that: (1) the level of cytotoxicity for H-2^b incompatible cells was similar in LS and B10.D2 mice; (2) CTL recognizing host DBA/2 mHAgs, whose expression is restricted to the spleen or is shared between spleen and P815 cells, were partially unresponsive in LS mice; (3) P815 injection into LS mice predominantly generated CTL specific for antigens restricted to P815 cells, the repertoire of which was not tolerized. Characterization of TCR βchain showed that the diversity of Vβand Jβusage by CD8⁺ T cells activated after P815 injection is considerably restricted in LS mice, compared to B10.D2 donor mice. These results indicated that the GVL effect in LS mice involved mainly T cells specific for tissue-restricted antigens expressed on P815 cells and not on normal DBA/2 spleen cells. In addition, the absence of GVHD may be attributed to the unresponsiveness of CD8⁺ CTL specific for host mHAgs expressed on DBA/2 spleen cells.