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

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.