Abstract

Background: A key step in the rejection process is the transendothelial migration of Ag-specific effector and memory T cells into the graft. It is generally assumed that this step is mediated by Gai-coupled chemokine receptor signaling. Here, we revisited this paradigm by investigating the migration of polyclonal and monoclonal effector and memory T cells to vascularized transplants in the presence or absence of Gai signaling. Methods: B6 CD4 and CD8 polyclonal effector and memory T cells primed against BALB/c were treated with pertussis toxin (PTx) to block Gai signaling or not and co-transferred to B6 wt or alymphoplastic (aly/aly) mice 2 days after transplanting BALB/c hearts. Ag(OVA)-specific (OT-I) and non-specific (P14) CD8 effector/memory T cells were transferred to B6 recipients of B6 Act-OVA or wt heart or kidney grafts to investigate the role of cognate Ag in T cell migration. Migration of transferred T cells to the grafts was quantified by flow cytometry and 2-photon intravital microscopy using congenic markers, MHC-tetramers and cell tracker reagents. Results: PTx-treated and untreated polyclonal effector and memory T cells migrated to and rejected heart allografts in equal numbers and with the same tempo. Ag(OVA)-specific (OT-I) effector/memory T cells migrated only to heart grafts that expressed the cognate Ag (OVA) and their migration was not inhibited by PTx. Non-specific (P14) T cells, on the other hand, did not migrate to Act-OVA grafts unless Ag-specific (OT-I) T cells were present, and their migration was abrogated by PTx. Intravital imaging of transplanted Act-OVA kidneys established that PTx did not inhibit the firm adhesion or transendothelial migration of Ag-specific (OT-I) effector/memory T cells. In contrast, adhesion and transmigration of non-specific (P14) T cells occurred only if their Gai signaling was intact. Conclusion: In contrast to the chemokine-dependent paradigm, the migration of Ag-specific effector/memory T cells to vascularized allografts requires interaction with cognate Ag and is independent of chemokine signaling. Entry of non-specific effector/memory T cells, on the other hand, requires chemokines but occurs only if Ag-specific T cells are present. These findings underscore the critical role of cognate Ag in directing the entry of primed T cells to non-lymphoid tissues and suggest novel mechanisms for their transmigration across the endothelium.

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