Dendritic cells (DC) are rare leukocytes uniquely specialized for immune surveillance and the induction of primary immune responses. Traditionally regarded as the instigators of rejection, it is now recognized that either donor or host DC, particularly those that are immature, can also modulate immune reactivity and the induction of tolerance to foreign and self antigens. Recent proposals attribute this dichotomy of DC function in part to the existence of distinct DC subsets, although it is likely that the state of DC maturation and/or activation and local environmental factors also play significant roles. DC can be divided into distinct subpopulations that differ in phenotype, function and microenvironmental location. Although human and mouse DC subtypes are phenotypically disparate, there is clear evidence for similar functional specializations. Mouse CD8a⁺ DC (distinct from classically described myeloid DC) are the principal DC subtype identified in the thymus and have been implicated in the regulation of central and peripheral tolerance. Consistent with these reports, our preliminary observations have demonstrated that CD8a⁺ DC possess an innate capacity to impair donor-specific reactivity and prolong organ allograft survival. The immune-regulatory effect is observed using CD8a⁺ DC isolated directly from donor spleen, without requiring in vitro culture or sophisticated manipulation such as genetic engineering. We hypothesize that CD8a⁺ donor DC suppress allo-antigen specific responses and prolong allograft survival in the absence of exogenous immunosuppression, either through the induction of regulatory T cells, and/or the deletion of alloreactive T cells. Testing of this hypothesis will place the investigators in a powerful position to develop a DC-based, alloantigen-specific strategy for the reliable induction of tolerance.