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

作者：McAlees Jaclyn W; Lajoie Stephane; Dienger Krista; Sproles Alyssa A; Richgels Phoebe K; Yang Yanfen; Khodoun Marat; Azuma Miyuki; Yagita Hideo; Fulkerson Patricia C; Wills Karp Marsha; Lewkowich Ian P^*

来源：European Journal of Immunology, 2015, 45(4): 1019-1029.

DOI：10.1002/eji.201444778

• Airway hyperreactivity
• Asthma
• Cytokines
• PD-1
• PD-L1
• Th1 response
• Th2 response
• Th17 response

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, naive PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in WTcells 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 naive Tcells 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.

• 出版日期2015-4