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 4

Cross-dressing of host DCs with donor MHC class I–peptide complexes in kidney allografts.

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Cross-dressing of host DCs with donor MHC class I–peptide complexes in k...
(A) (B6×BALB/c)F1.Act-mOVA (F1.OVA) (H-2Kb/d) kidneys were transplanted to B6 H-2Kb–sufficient (H-2Kb/b) WT (n = 5–6) or B6 H-2Kb-deficient (H-2K–/–) (n = 4–6) recipients. 1 × 107 B6.Rag–/– OT-I CD8+ effector T cells, which recognize the OVA peptide SIINFEKL bound to H-2Kb, were transferred i.v. 2 days later. Grafts were analyzed 8 or 58 days after OT-I transfer. Control and experimental groups are shown in Table 2. (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+) DCs. Representative images from each group from day 10 grafts shown. On average, 426 (range = 153–784) and 3068 (range = 547–10366) cells were analyzed per animal on day 10 and day 60, respectively. (C) Proportion of host DCs positive for 1 or more spots of either H-2Kd or H-2Kb–SIINFEKL. Each data point represents analysis of 1 transplanted animal. (D) Histological analysis of grafts from cross-dressing and control groups removed on day 10 and day 60. Photomicrographs show examples of arteritis, tubulitis, intimal hyperplasia, and interstitial fibrosis and tubular atrophy (IFTA) in grafts from cross-dressed group. Scale bars: 50 μm. Bar graphs depict quantitation of Banff grades and serum creatinine on day 10 and day 60. Dashed line denotes lower detection limit for creatinine (<0.2 mg/dl). (E) Flow cytometric analysis of cellular infiltrate in allografts removed on day 10 and day 60 from cross-dressing and positive control groups. *P < 0.05; ***P < 0.001, 2-tailed unpaired t test.