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 November 25, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI125773.
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Categories: 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 1

Host DCs are extensively cross-dressed with donor MHC class I–peptide complexes in islet allografts.

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Host DCs are extensively cross-dressed with donor MHC class I–peptide co...
(A) F1.OVA H-2Kb–sufficient (H-2Kb/d) or F1.OVA H-2Kb-deficient (H-2Kd/–) islets were transplanted under the kidney capsule of B6.CD11c-YFP H-2Kb–sufficient (H-2Kb/b) or B6.CD11cYFP H-2Kb–deficient (H-2Kb–/–) recipients. 5 × 106 B6.Rag–/–.DsRed OT-I CD8+ effector T cells, which recognize the OVA peptide SIINFEKL bound to H-2Kb, were transferred i.v. 6 days later. One day after OT-I transfer, grafts were analyzed by imaging flow cytometry (B) and 2P-IVM (Figure 2). Control and experimental groups are shown in Table 1. (B) Leukocytes were isolated from transplanted allografts and analyzed by ImageStream. Intact H-2Kb–SIINFEKL complexes and donor H-2Kd molecules were identified as discreet spots on surface of host (CD11c-YFP) DCs. Representative images from each group are shown. (C) Proportion of host DCs positive for 1 or more spot of either H-2Kd or H-2Kb–SIINFEKL. In all groups, the majority of cells (~90%) carried only one spot, while the remainder had 2 to 5 spots (data not shown). The majority of DCs in the cross-dressing and control groups carried both MHC class I molecules. Each data point represents analysis of 1 transplanted animal. On average, 1071 (range = 100–3900) cells were analyzed per animal. **P < 0.01; ***P < 0.001; ****P < 0.0001. One-way ANOVA with Tukey’s multiple comparison test.