Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Abstract

Programmed death-1 ligand 2 (PD-L2) is a ligand for programmed death-1 (PD-1), a receptor that plays an inhibitory role in T cell activation. Since previous studies have shown upregulation of PD-L2 expression by Th2 cytokines, and asthma is driven by a Th2 response, we hypothesized that PD-L2 might be involved in regulation of the immune response in this disease. We have found that lungs from asthmatic mice had sustained up-regulation of PD-1 and PD-L2, with PD-L2 primarily on dendritic cells. Although addition of PD-L2-Fc in vitro led to decreased T cell proliferation and cytokine production, administration of PD-L2-Fc in vivo in a mouse asthma model resulted in elevated serum IgE levels, increased eosinophilic and lymphocytic infiltration into bronchoalveolar lavage fluid, higher number of cells in the draining lymph nodes, and production of IL-5 and IL-13 from these cells. Although PD-1 was expressed on regulatory T cells, PD-L2-Fc did not affect regulatory T cell activity in vitro. This study provides in vivo evidence of an exacerbated inflammatory response following PD-L2-Fc administration and indicates a potential role for this molecule in Th2-mediated diseases such as asthma.

Concomitant Inhalation of Cigarette Smoke and Aerosolized Protein Activates Airway Dendritic Cells and Induces Allergic Airway Inflammation in a TLR-Independent Way

“…This is reminiscent of the previously described increase in PDL2 on airway DCs of OVA-alum-sensitized/OVA aerosol-challenged allergic mice (46) and might thus be a characteristic feature of allergic immune responses. PDL2 costimulation during allergen priming and challenge was shown to exacerbate immune and inflammatory allergic responses in mice, supporting a Th2-potentiating function (47). It has also been proposed that Th2 cells specifically regulate PDL2 expression on DCs via reverse signaling (48,49).…”

The Role of Costimulatory Molecules in Allergic Disease and Asthma

“…In addition, administration of the sHIgM12 antibody (an antibody inducing reverse signaling through PD-L2) in a mouse model of allergic asthma blocks the development of AHR [50]. An additional study demonstrates that administration of PD-L2-Fc in a mouse model of allergic asthma resulted in elevated levels of serum IgE and increased eosinophilic and lymphocytic infiltration into the bronchoalveolar lavage fluid [51]. These studies emphasize the pivotal role of PD-L2 in the development of allergic asthma.…”

TIM-1 regulates macrophage cytokine production and B7 family member expression

“…The B7 family member PD-L2 has also been implicated in the regulation of AHR [18,19]. Administration of anti-PD-L2 during allergen challenge, but not sensitization, decreases IFN-␥ production but increases IL-5 and IL-13 production by T cells.…”

“…In light of our current study, it is possible that expression of TIM-1 on Th2 T cells plays a role in PD-L2 expression by macrophages. In vivo administration of PD-L2 enhances inflammatory responses during AHR [18]. The interaction between Th2 T cells and macrophages may form a positive feedback loop that lead maintains the Th2 T cell phenotype.…”