Hurrell et al. demonstrated the role of the PD-1/PD-L2 axis in the maintenance of immunoregulatory Foxp3+ peripheral Tregs (pTregs) and airway immune tolerance. PD-L2 binding to PD-1 on Tregs increased Foxp3 expression and IL-10 secretion in vitro. Mice lacking PD-L2 showed impaired TCA cycle and mitochondrial respiration, lower numbers of splenic pTregs at steady state, produced less IL-10 upon activation, had reduced suppressive activity and increased airway hyperreactivity. Adoptive transfer of PD-L2high dendritic cells restored pTreg numbers and pyruvate treatment partially restored IL-10 production and airway tolerance.
Contributed by Shishir Pant
ABSTRACT: Regulatory T (Treg) cells are central to limit immune responses to allergens. Here we show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway hyperreactivity, in particular by limiting pTreg numbers and function. In vitro, PD-1/PD-L2 interactions increase iTreg numbers and stability. In mice lacking PD-L2 we find lower numbers of splenic pTregs at steady state, producing less IL-10 upon activation and with reduced suppressive activity. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2(high) dendritic cells to PD-L2(KO) mice. Functionally, activated pTregs lacking PD-L2 show lower Foxp3 expression, higher methylation of the Treg-Specific Demethylation Region (TSDR) and a decreased Tricarboxylic Acid (TCA) cycle associated with a defect in mitochondrial function and ATP production. Consequently, pyruvate treatment of PD-L2(KO) mice partially restores IL-10 production and airway tolerance. Together, our study highlights the importance of the PD-1/PD-L2 axis in the control of metabolic pathways regulating pTreg Foxp3 stability and suppressive functions, opening up avenues to further improve mucosal immunotherapy.