Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation
Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I. Shoushtari, Reza Dana
Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I. Shoushtari, Reza Dana
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Research Article Immunology Ophthalmology

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation

Abstract

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin–activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Authors

Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I. Shoushtari, Reza Dana

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Figure 7

The effect of migratory CD103+ DC1 in modulating CD11b+ DC2 in the DLN and graft site.

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The effect of migratory CD103+ DC1 in modulating CD11b+ DC2 in the DLN a...
CD11b+ DC2 were analyzed by flow cytometry (gating strategy for grafted cornea and conjunctiva shown in Supplemental Figure 1 and for DLN shown in Supplemental Figure 2). (A–C) Expression of CD86 and IL-12 in the DLN of LR and HR transplanted mice treated with either anti–M290-SAP or anti–IgG-SAP (A), HR WT treated with either iDC1 or PBS and RAG–/– transplanted mice (B), and LR WT and RAG–/– transplanted mice treated with ADWA-11 antibody or IgG control (C) are shown. (D–I) In parallel, flow cytometry was performed on single-cell suspensions from the grafted corneas (D–F) and conjunctivae (G–I) of the same mice as described in A–C. Each symbol (A–I) indicates an individual mouse. Plots represent the mean (± SEM). One-way ANOVA with Bonferroni correction was used. All results are of 1 experimental set of animals with no repetitions.