Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance

Dendritic cells (DCs) are pivotal antigen-presenting cells and serve a unique role in initiating immunity. To test the hypothesis that pre-immunization of recipient with certain DC subsets of donor origin can influence graft outcome, we have studied the effects of immunization with allogeneic CD4⁺CD8^-CD11c⁺ dendritic cell (CD4⁺ DC) and CD4^-CD8⁺ CD11c⁺ dendritic cell (CD8⁺ DC) on the allograft response. Although both immature CD4⁺DC and CD8⁺DC subsets from DBA/2 were able to prime naive allogeneic C57BL/6 (B6) T cells in mixed lymphocyte reaction (MLR), CD8⁺DC exerted more vigorous alloimmune responses than CD4⁺DC did. Also, CD4⁺DC-driven allogeneic T cell response was attenuated more significantly by anti-CD154 mAb than CD8⁺DC-driven response. Consistent with the MLR results, combined pre-treatment with CD4⁺DC, but not CD8⁺DC, plus anti-CD154 mAb produced donor strain-specific long-term graft survival and induced tolerance while treatment with CD8⁺DC plus anti-CD154 mAb created minimal prolongation of allograft survival in a pancreas islet transplant model (DBA/2→B6). The beneficial effects exerted by CD4⁺ DC and anti-CD154 mAb pre-treatment were correlated with T_h1 to T_h2 immune deviation and with the amplified donor-specific suppressive capacity by recipient CD4⁺CD25⁺ T cells. These findings highlight the capacity of CD4⁺DC to modulate alloimmune responses, and suggest therapeutic approaches for the induction of donor-specific tolerance.