Differential Involvement of Programmed Cell Death Ligands in Skin Immune Responses

J Invest Dermatol. 2022 Jan;142(1):145-154.e8. doi: 10.1016/j.jid.2021.06.026. Epub 2021 Jul 24.


PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Calcitriol / analogs & derivatives
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dermatitis, Atopic / immunology*
  • Dermatitis, Contact / immunology*
  • Dinitrofluorobenzene
  • Disease Models, Animal
  • Humans
  • Imiquimod
  • Inflammation / immunology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Ligand 2 Protein / genetics
  • Programmed Cell Death 1 Ligand 2 Protein / metabolism*
  • Psoriasis / immunology*
  • Skin / immunology
  • Skin / pathology*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Th2 Cells / immunology*


  • B7-H1 Antigen
  • Cytokines
  • Pdcd1lg2 protein, mouse
  • Programmed Cell Death 1 Ligand 2 Protein
  • calcipotriene
  • Dinitrofluorobenzene
  • Calcitriol
  • Imiquimod