Cognate antigen directs CD8+ T cell migration to vascularized transplants
Jeffrey M. Walch, … , Geoffrey Camirand, Fadi G. Lakkis
Jeffrey M. Walch, … , Geoffrey Camirand, Fadi G. Lakkis
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2663-2671. https://doi.org/10.1172/JCI66722.
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Cognate antigen directs CD8+ T cell migration to vascularized transplants

Abstract

The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration — integrin-mediated firm adhesion followed by transendothelial migration — are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow–derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gαi, but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow–derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.

Authors

Jeffrey M. Walch, Qiang Zeng, Qi Li, Martin H. Oberbarnscheidt, Rosemary A. Hoffman, Amanda L. Williams, David M. Rothstein, Warren D. Shlomchik, Jiyun V. Kim, Geoffrey Camirand, Fadi G. Lakkis

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Figure 5

Presentation of cognate antigen by either graft endothelium or bone marrow–derived APCs is sufficient for the transmigration of effector T cells.

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Presentation of cognate antigen by either graft endothelium or bone marr...
OT-I effectors were imaged as described in Figure 3. (A) Visualization and enumeration of OT-I cells arrested in B6-OVA kidney grafts that lack H-2KB expression on the endothelium (WT CD11c-YFP+→H2kb–/– chimeric graft to WT CD11c-YFP+ recipient), APCs (H2kb–/–→WT chimeric graft to H2kb–/– recipient), or both (H2kb–/– graft to H2kb–/– recipient) (n = 7–10 videos/group, 2–3 independent experiments). Volume-rendered representative time point images (top) show arrested OT-I cells (red); green cells (left) are YFP+ DCs; blood vessels are labeled in blue. Time projections (bottom) depict OT-I cells (red) tracked over approximately 30 minutes. (B and C) Percent OT-I cells that had either firmly adhered to (B) or transmigrated across (C) the capillary wall of B6-OVA kidney grafts in the same experimental groups in A. (D–F) Motility parameters — median velocity (D), displacement (E), and arrest coefficients (F) — of OT-I cells imaged in B6-OVA kidney grafts that lack H-2KB expression on the endothelium (n = 168), APCs (n = 206), or both (n = 77). Results are mean ± SEM. ***P < 0.001. Scale bars: 50 μm.