Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts
Andrew D. Hughes, … , Martin H. Oberbarnscheidt, Fadi G. Lakkis
Andrew D. Hughes, … , Martin H. Oberbarnscheidt, Fadi G. Lakkis
Published January 2, 2020; First published November 25, 2019
Citation Information: J Clin Invest. 2020;130(1):287-294. https://doi.org/10.1172/JCI125773.
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Research Article Immunology Transplantation

Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts

Abstract

Activation of host T cells that mediate allograft rejection is a 2-step process. The first occurs in secondary lymphoid organs where T cells encounter alloantigens presented by host DCs and differentiate to effectors. Antigen presentation at these sites occurs principally via transfer of intact, donor MHC-peptide complexes from graft cells to host DCs (cross-dressing) or by uptake and processing of donor antigens into allopeptides bound to self-MHC molecules (indirect presentation). The second step takes place in the graft, where effector T cells reengage with host DCs before causing rejection. How host DCs present alloantigens to T cells in the graft is not known. Using mouse islet and kidney transplantation models, imaging cytometry, and 2-photon intravital microscopy, we demonstrate extensive cross-dressing of intragraft host DCs with donor MHC-peptide complexes that occurred early after transplantation, whereas host DCs presenting donor antigen via the indirect pathway were rare. Cross-dressed DCs stably engaged TCR-transgenic effector CD8+ T cells that recognized donor antigen and were sufficient for sustaining acute rejection. In the chronic kidney rejection model, cross-dressing declined over time but was still conspicuous 8 weeks after transplantation. We conclude that cross-dressing of host DCs with donor MHC molecules is a major antigen presentation pathway driving effector T cell responses within allografts.

Authors

Andrew D. Hughes, Daqiang Zhao, Hehua Dai, Khodor I. Abou-Daya, Roger Tieu, Rayan Rammal, Amanda L. Williams, Douglas P. Landsittel, Warren D. Shlomchik, Adrian E. Morelli, Martin H. Oberbarnscheidt, Fadi G. Lakkis

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Figure 2

Cross-dressed host DCs make stable contacts with Ag-specific, CD8+ effector T cells in islet allografts.

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Cross-dressed host DCs make stable contacts with Ag-specific, CD8+ effec...
2P-IVM was performed on islet grafts 24 hours after transferring OT-I effectors as outlined in Figure 1A. Three mice were imaged per group with multiple locations (between 2 and 6) imaged per graft. (A) Equal infiltration of allografts with OT-I effectors (red) in all groups. Allografts were well vascularized (magenta) at the time of imaging and had abundant host-derived YFP+ DCs (green) in and around islets (blue). Supplemental Video 1, corresponding to the micrographs, illustrates dynamic behavior of OT-I in the grafts. Each data point in the plot represents total OT-I counts in 1 graft location imaged. Ctrl, control. (B) OT-I paths over 5-minute imaging period (blue dragon tails) and contact with DCs (white surfaces) are shown in the photomicrographs and in Supplemental Video 2. Quantification of OT-I DC contacts per image volume and contact time are shown in the graphs. Each data point in the first plot represents total OT-I DC contacts counts in 1 graft location imaged. Each data point in the second plot represents contact time for each OT-I cell (all cells that made contact with DCs for more than 90 seconds were analyzed per location imaged; range = 259–1450 cells/location). (C) Arrest of OT-I effectors in the cross-dressing group is depicted by the shorter paths they took compared with the indirect group (photomicrographs with paths tracked over a 30-minute period) and by the quantitation of mean speed and arrest coefficients (graphs). The arrest coefficient is the proportion of time in which a cell moves less than 2 μm/min. Each data point in the plots represents a single OT-I cell (all cells were analyzed per location imaged; range = 987–2361 cells/location). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Random intercept model with the Bonferroni’s multiple comparison adjustment for pairwise comparisons between group means was applied to avoid pseudoreplication errors. Comparisons not shown in Figure 2, B and C, were not significant. Scale bars: 50 μm (A); 40 μm (B); 100 μm (C).