The role of direct presentation by donor dendritic cells in rejection of minor histocompatibility antigen-mismatched skin and hematopoietic cell grafts

Background.: The success of transplantation is hampered by rejection of the graft by alloreactive T cells. Donor dendritic cells (DC) have been shown to be required for direct priming of immune responses to antigens from major histocompatibility complex-mismatched grafts. However, for immune responses to major histocompatibility complex-matched, minor histocompatibility (H) antigen mismatched grafts, the magnitude of the T-cell response to directly presented antigens is reduced, and the indirect pathway is more important. Therefore, we aimed to investigate the requirement for donor DC to directly present antigen from minor H antigen mismatched skin and hematopoietic grafts. Methods.: Langerhans cell- or conventional (c)DC-depleted skin or hematopoietic cells from male DC-specific diphtheria toxin receptor mice were grafted onto, or injected into, syngeneic female recipients, and survival of the male tissue was compared with nondepleted tissue. Activation of the alloreactive immune response was tracked by the expansion of T cells specific for male HY-derived epitopes. Results.: Our data demonstrate that depletion of donor Langerhans cell, dermal cDC, or both from skin grafts prolongs their survival but does not prevent rejection. Extended survival correlates with delayed expansion of HY peptide-specific CD8⁺ T cells. In addition, depletion of donor cDC delays rejection of male hematopoietic cells. Conclusions.: Our results demonstrate for the first time that direct presentation of minor H antigens by donor DC is required for efficient rejection of skin and hematopoietic grafts by CD8⁺ T cells. But, in the absence of donor DC, indirect presentation of minor antigens is sufficient to mediate the response.