Differential control of CD4(+) T-cell subsets by the PD-1/PD-L1 axis in a mouse model of allergic asthma

Eur J Immunol. 2015 Apr;45(4):1019-29. doi: 10.1002/eji.201444778. Epub 2015 Feb 26.


Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD-1/PD-L1 has distinct influences on different CD4(+) T-cell subsets. PD-1/PD-L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2-type immune response, but by allowing the development of a concomitant Th17-type immune response. Supporting differential CD4(+) T-cell responsiveness to PD-1-mediated inhibition, naïve PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4(+) T-cell subsets respond differentially to PD-1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD-1 family members. As the PD-1/PD-L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD-1/PD-L1 regulatory axis in some individuals.

Keywords: Airway hyperreactivity; Asthma; Cytokines; PD-1/PD-L1; Th1 response; Th17 response; Th2 response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Asthma / immunology*
  • B7-H1 Antigen / immunology*
  • Cell Differentiation / immunology
  • Cell Movement / immunology
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Interleukin-12 / blood
  • Lung / cytology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Ligand 2 Protein / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*
  • Pyroglyphidae / immunology
  • Spleen / cytology
  • T-Lymphocyte Subsets / immunology
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Th2 Cells / cytology
  • Th2 Cells / immunology


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Cytokines
  • Pdcd1 protein, mouse
  • Pdcd1lg2 protein, mouse
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Interleukin-12