Augmentation of Recipient Adaptive Alloimmunity by Donor Passenger Lymphocytes within the Transplant

• Donor CD4 T cells provide cognate, but peptide-degenerate, help to all host B cells
• Antibody specificity is determined by concurrent B cell receptor ligation
• Passenger donor CD4 T cells can therefore augment host alloantibody responses
• Host NK cell allorecognition is critical for preventing this augmentation

SummaryChronic rejection of solid organ allografts remains the major cause of transplant failure. Donor-derived tissue-resident lymphocytes are transferred to the recipient during transplantation, but their impact on alloimmunity is unknown. Using mouse cardiac transplant models, we show that graft-versus-host recognition by passenger donor CD4 T cells markedly augments recipient cellular and humoral alloimmunity, resulting in more severe allograft vasculopathy and early graft failure. This augmentation is enhanced when donors were pre-sensitized to the recipient, is dependent upon avoidance of host NK cell recognition, and is partly due to provision of cognate help for allo-specific B cells from donor CD4 T cells recognizing B cell MHC class II in a peptide-degenerate manner. Passenger donor lymphocytes may therefore influence recipient alloimmune responses and represent a therapeutic target in solid organ transplantation.

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