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.
Author Info: (1) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (2) Department of Molecular Microbiology
Author Info: (1) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (2) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (3) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (4) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (5) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (6) Department of Immunology, Harvard Medical School, Boston, MA, USA. (7) Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. akbari@usc.edu.
