Thymic Selection and Anti-Leukemic Effect of CD8 T Cells Specific for Hematopoietic Cell-Restricted Minor Histocompatibility Antigen, H60

Abstract

Allogeneic bone marrow transplantation (allo-BMT) in hematologic malignancy can induce graft-versus-leukemia (GVL) effect, but its mechanism remains to be elucidated. Conventionally, it has been believed that mature donor T cells included in the donor bone marrow population induce GVL effect rather than the donor T cells newly generated in the recipient thymus, because donor T cells developed in the recipient thymus would undergo negative selection against host allo-antigens. However, recently, it was reported that thymus-derived donor T cells might induce chronic graft-versus-host-disease (GVHD) after allo-BMT. Also, several reports suggested that some T cells specific for peripheral tissue-restricted antigens are incompletely deleted in the thymus. Therefore, it would be necessary to examine whether donor T cells developed in the recipient thymus would be completely deleted in allo-BMT settings, without contributing to GVL effect. Thus, we intended to study this issue using MHC-matched, minor histocompatibility antigen (MiHA)-mismatched allo-BMT mouse model, which represents the current clinical BMT settings. A MiHA whose expression is limited to hematopoietic cells was chosen as a model allo-antigen to be studied because donor T cells specific for the hematopoietic cell-restricted antigen (HRA) would attack hematopoietic tumor cells without induction of GVHD, of which target organs are usually solid organs. Nonetheless, thymic negative selection of HRAs has never been studied in detail. <br/> In this study, using a mouse MiHA H60, of which expression is restricted to hematopoietic cells, I established a H60-specific TCR transgenic mouse line (J15). Surprisingly, I found that H60-specific J15 T cells were not fully deleted in the thymus of H60-expressing mice and escaped from the negative selection as low-avidity T cells. In an allo-BMT setting, H60-specific donor J15 T cells generated in the H60(+) recipient thymus underwent incomplete thymic deletion and developed into mature T cells with intact effector function. Importantly, they led to regression of H60(+) hematological tumors inoculated with minimal GVHD. These effects were also observed with polyclonal H60-specific donor T cells in the non-transgenic setting. Thus, T cells specific for HRAs developed in the thymus can be matured, and this phenomenon can be applied to design effective BMT strategy to achieve GVL without GVHD.<br/>