PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production

Abstract

Studies examining the role of PD-L2/PD-1 in asthma have yielded conflicting results. To clarify its role, we examined PD-L2 expression in biopsies from human asthmatics and lungs of aeroallergen-treated mice. PD-L2 expression in bronchial biopsies correlated with the severity of asthma. In mice, allergen exposure increased PD-L2 expression on pulmonary myeloid dendritic cells, and PD-L2 blockade diminished allergen-induced airway hyperresponsiveness (AHR). In contrast, PD-1 blockade had no impact, suggesting that PD-L2 promotes AHR in a PD-1-independent manner. Decreased AHR was associated with enhanced serum IL-12 p40 and in vitro stimulation of DCs with allergen and PD-L2-Fc reduced IL-12 p70 production, suggesting that PD-L2 inhibits allergen-driven IL-12 production. In our model, IL-12 did not diminish Th2 responses, but rather directly antagonized IL-13-inducible gene expression, highlighting a novel role for IL-12 in regulation of IL-13 signaling. Thus, allergen-driven enhancement of PD-L2 signaling through a PD-1-independent mechanism limits IL-12 secretion, exacerbating AHR.

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

“…PD-L2 is an enigmatic molecule reported to positively and negatively regulate T cells (95–101); its effects on B cells are less well-defined. PD-L2 expression is restricted to B-1 cells, memory B cells raised in response to T cell–dependent Ags, macrophages, and dendritic cells (47, 101, 102).…”

Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation

“…Whereas both molecules upregulate upon challenge,28 Akbari et al 9 showed that PD-L1 −/− mice had reduced BHR, while PD-L2 −/− mice were protected against ovalbumin-induced experimental asthma. Recently, Lewkovitch et al demonstrated that a high PD-L2 expression on lung mDCs in humans correlated with disease severity8 and peaked in mice around 24 h post challenge while PD-L2 (and not PD-L1) blockade resulted in decreased NSBHR and inhibition of IL-13-induced gene expression. However, as PD-L2 blockade failed to inhibit Th2 cytokine expression, the authors postulated about unidentified ligand(s) to PD-L2 that might have different effects.…”

“…Besides their ability to present allergens to naïve T cells, mDCs are able to shape the immune response through the secretion of cytokines and expression of costimulatory molecules. The role of some costimulatory molecules has been recently explored in human asthma,7 including the first and second ligands to programmed death-1 (PD-L1 and PD-L2)8 9 and the ligand to immune costimulator,10 as factors involved in the intrinsic pro-Th2 bias of mDCs from patients with asthma 11 12. mDCs from patients with allergic asthma also have an intrinsic propensity to respond to proallergic epithelial cytokines such as thymic stromal lymphopoietin 13…”

Pathobiology of Severe Asthma

“…Finally, most murine allergic asthma models have a strong parenchymal component that is not seen in human disease. Although newer murine models have been developed with the hope of better reflecting SA (or its phenotypes), the relation to human SA has not yet been confirmed (32,33).…”