PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability

Benjamin P. Hurrell, Doumet Georges Helou, Emily Howard, Jacob D. Painter, Pedram Shafiei-Jahani, Arlene H. Sharpe and Omid Akbari ()
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Benjamin P. Hurrell: University of Southern California
Doumet Georges Helou: University of Southern California
Emily Howard: University of Southern California
Jacob D. Painter: University of Southern California
Pedram Shafiei-Jahani: University of Southern California
Arlene H. Sharpe: Harvard Medical School
Omid Akbari: University of Southern California

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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-L2high dendritic cells to PD-L2KO 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-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.

Date: 2022
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DOI: 10.1038/s41467-022-32899-5

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