Infiltration of the graft with host effector T cells after transplantation is a key step in the pathogenesis of both acute and chronic rejection. Recent data indicate that effector T cell migration into primary vascularized organ transplants such as hearts and kidneys is driven by donor (cognate) antigen recognition and not via Gai-coupled chemokine receptor signaling. Whether the same is true for neovascularized pancreatic islet allografts, in which the blood vessels are of host origin, is not known. To answer this question, we co-transferred pertussis toxin (PT)-treated and untreated TCR-transgenic (OT-1) effector T cells into B6 recipients 7-10 days after transplanting B6-Act-OVA or B6 islet grafts under the kidney capsule. PT irreversibly blocks Gαi-dependent signaling. In a parallel experiment, PT-treated or untreated polyclonal effector T cells, generated in vitro against BALB/c splenocytes, were co-transferred into B6 recipients of BALB/c islet allografts. Grafts were imaged 20-24 hours after T cell transfer by two-photon intravital microscopy. We observed that B6-Act-OVA grafts were heavily infiltrated with OT-1 effector T cells irrespective of whether they were or were not pre-treated with PT (5-10 million vs. 5-10 million, respectively, n = 3 ), while B6 grafts, which lack the cognate antigen recognized by OT-1 T cells, were free of infiltrate (<1 cell/million transferred). Analogous results were obtained when PT-treated and untreated polyclonal effector T cells were transferred into B6 recipients of BALB/c grafts; however, overall polyclonal T cell numbers present in the graft were less than those observed when TCR-tg T cells were transferred. These results indicate that, similar to heart and kidney transplants, islet allograft infiltration with host effector T cells is driven by donor antigen and not by Gαi-coupled chemokine receptor signaling. The paradigm of antigen-driven effector T cell migration is therefore generalizable to both primary vascularized grafts, in which donor antigens are abundantly expressed on the endothelium, and neovascularized cellular grafts whereby the endothelium is of host origin.

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