Interferon-beta (IFNb) Reprograms Pathogenic Lung Dendritic Cells in Human Chronic Lung Allograft Dysfunction (CLAD)

Abstract

<h3>Purpose</h3> Dendritic cells (DC) are central to the induction and maintenance of T regulatory cells (T-regs) and lung allograft tolerance. We previously identified tumor necrosis factor 2 positive DC (TNFR2⁺DC) as a subset of lung resident DC responsible for antigen-specific Th2 mediated response and inflammation in mice model of asthma. Interestingly, TNFR2⁺DC is plastic and intranasal administration of IFNβ reprograms TNFR2⁺DC to generate regulatory T-cells and reverses lung inflammation in mice. We set out to characterize TNFR2⁺DC and the response to IFNβ in healthy human donor and CLAD lungs. <h3>Methods</h3> We evaluated single-cell suspensions from the unused healthy human donor lungs from the lobar transplantation, and CLAD explant lung tissue from patients undergoing re-transplantation. Identification of TNFR2⁺DC populations and the response to IFNβ (200ng IFNβ, R&D systems INC. MN, USA) were investigated with flow cytometry analysis. <h3>Results</h3> We successfully identified the TNFR2⁺DC population in healthy donor and CLAD lung tissues (n=4/group) (Figure 1A). The healthy lung TNFR2⁺DC constitutively express TGFβ1, IDO-1, and Arg-1, which has a similar phenotype to tolerogenic DC in mouse lungs. Conversely, TNFR2⁺DC from CLAD patients had decreased TGFβ1, Arg-1, PD-L1, but increased IL-4 and IL-23 expression (Figure 1B). Treatment with IFNβ increased TGFβ1, Arg1, and decreased IL-4 expression in CLAD TNFR2⁺DC. Thus, similar to mice, treatment with IFNβ reprograms pathogenic TNFR2⁺DC in CLAD to phenotypically tolerogenic DC (Figure 1C). <h3>Conclusion</h3> We identified TNFR2⁺DC in healthy human donor lung and CLAD. Healthy human donor lung has a phenotypically tolerogenic TNFR2⁺DC. Conversely, TNFR2⁺DC in CLAD shows inflammatory markers, and treatment with IFNβ reprograms pathogenic DC to a tolerogenic phenotype. Further studies are required to assess the utility of TNFR2⁺DC plasticity for achieving lung allograft tolerance.