W102 - PD-L2 Maintains Metabolic Function and Stability of Regulatory T Cells

Georges Doumet Helou – University of Southern California; Emily Howard – University of Southern California; Pedram Shafiei-Jahani – University of Southern California; Arlene Sharpe – Harvard University; Omid Akbari – University of Southern California

Abstract Text: Regulatory T (Treg) cells are central to limit immune responses to allergens. Our studies show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway hyperreactivity, in particular by limiting peripheral Treg (pTreg) numbers and function. Ex vivo, PD-1/PD-L2 interactions increase iTreg numbers and stability, notably by promoting metabolic activity, demethylation of the TSDR region and Foxp3 expression. 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 activities. In particular, there were no differences in thymic Treg progenitors nor differences in thymic Treg (tTreg) numbers, suggesting for a role for PD-L2 exclusively in the periphery. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2high dendritic cells to PD-L2KO mice, without affecting tTreg numbers. Functionally, our transcriptomic, epigenetic and bioenergetic studies show that activated pTregs isolated from mice lacking PD-L2 have lower Foxp3 expression, higher methylation of the TSDR region and a decreased TCA cycle associated with a defect in mitochondrial function. Consequently, adoptively transferred WT induced Tregs (iTregs) to PD-L2KO recipient mice had a lower survival rate compared to controls, confirming that exogenous PD-L2 controls pTreg stability in vivo. Our metabolic studies further show that pyruvate treatment of PD-L2KO 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.