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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Benjamin P. Hurrell & Doumet Georges Helou & Emily Howard & Jacob D. Painter & Pedram Shafiei-Jahani & Arlene H. Sharpe & Omid Akbari, 2022. "PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32899-5
    DOI: 10.1038/s41467-022-32899-5
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    References listed on IDEAS

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    1. Inmaculada Martínez-Reyes & Navdeep S. Chandel, 2020. "Mitochondrial TCA cycle metabolites control physiology and disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Ye Zheng & Steven Josefowicz & Ashutosh Chaudhry & Xiao P. Peng & Katherine Forbush & Alexander Y. Rudensky, 2010. "Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate," Nature, Nature, vol. 463(7282), pages 808-812, February.
    3. Estelle Bettelli & Yijun Carrier & Wenda Gao & Thomas Korn & Terry B. Strom & Mohamed Oukka & Howard L. Weiner & Vijay K. Kuchroo, 2006. "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, Nature, vol. 441(7090), pages 235-238, May.
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