To evaluate the priming and trafficking of male Ag-reactive CD4+ T cells in vivo, we developed an adoptive transfer model, using Marilyn (Mar) TCR transgenic T cells that are specific for the H-Y minor transplantation Ag plus I-Ab. By manipulating donor and recipient strain combinations, we permitted the Mar CD4+ T cells to respond to the H-Y Ag after processing and presentation by recipient APCs (indirect pathway), or to the male Ag as expressed on donor APCs (direct pathway). Mar CD4+ T cells responding through the indirect pathway specifically proliferated and expressed activation markers between days 2 and 4 posttransplant, migrated to the graft 2–3 days before cessation of graft heartbeat, and were detected in close proximity to transplant-infiltrating recipient APCs. Intriguingly, adoptively transferred Mar T cells did not respond to male heart or skin grafts placed onto syngeneic MHC class II-deficient female recipients, demonstrating that activation of Mar T cell preferentially occurs through cognate interactions with processed male Ag expressed on recipient APCs. The data highlight the potency of indirect processing and presentation pathways in vivo and underscore the importance of indirectly primed CD4+ T cells as relevant participants in both the priming and effector phases of acute graft rejection.

Organ-specific injury after transplantation presents with a variety of clinical and pathological phenotypes, yet the factors influencing development of each outcome are poorly understood. Because primed T lymphocytes must re-encounter their antigen within the target organ to engage effector functions, we postulated that the cellular location of antigen within that organ could significantly impact the induced pathology. We challenged female Marilyn CD4 T-cell receptor transgenic mice, in which all T cells are specific for the male minor transplantation antigen, with male heart transplants expressing the rel- Naïve T lymphocytes are activated in secondary lymphoid organs in response to their specific antigens when such antigens are expressed on professional antigenpresenting cells (APCs) and in the context of appropriate co-stimulatory signals.

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MIF is not required for acute or chronic allograft rejection in mice. The findings raise questions about the role of DTH as an important mediator of cardiac allograft injury.

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