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Podoplanin negatively regulates CD4+ effector T cell responses
Anneli Peters, … , Estelle Bettelli, Vijay K. Kuchroo
Anneli Peters, … , Estelle Bettelli, Vijay K. Kuchroo
Published November 21, 2014
Citation Information: J Clin Invest. 2015;125(1):129-140. https://doi.org/10.1172/JCI74685.
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Research Article Immunology Article has an altmetric score of 8

Podoplanin negatively regulates CD4+ effector T cell responses

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Abstract

Podoplanin (PDPN, also known as Gp38) is highly expressed on the surface of lymphatic endothelial cells, where it regulates development of lymphatic vessels. We have recently observed that PDPN is also expressed on effector T cells that infiltrate target tissues during autoimmune inflammation; however, the function of PDPN in T cells is largely unclear. Here, we demonstrated that global deletion of Pdpn results in exaggerated T cell responses and spontaneous experimental autoimmune encephalomyelitis (EAE) in mice with a susceptible genetic background. In contrast, T cell–specific overexpression of PDPN resulted in profound defects in IL-7–mediated T cell expansion and survival. Consequently, these animals exhibited a more rapid resolution of CNS inflammation, characterized by a reduced effector CD4+ T cell population in the CNS. Mice harboring a T cell–specific deletion of Pdpn developed exacerbated EAE, with increased accumulation of effector CD4+ T cells in the CNS. Transcriptional profiling of naturally occurring PDPN+ effector T cells in the CNS revealed increased expression of other inhibitory receptors, such as Pd1 and Tim3, and decreased expression of prosurvival factors, including Il7ra. Together, our data suggest that PDPN functions as an inhibitory molecule on T cells, thereby promoting tissue tolerance by limiting long-term survival and maintenance of CD4+ effector T cells in target organs.

Authors

Anneli Peters, Patrick R. Burkett, Raymond A. Sobel, Christopher D. Buckley, Steve P. Watson, Estelle Bettelli, Vijay K. Kuchroo

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Figure 4

PdpnTG mice recover better from EAE.

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PdpnTG mice recover better from EAE.
(A and B) PdpnTG mice (line 552) an...
(A and B) PdpnTG mice (line 552) and their WT littermates were immunized with MOG/CFA and (A) monitored for clinical signs of EAE for 30 days. Linear regression analysis for the onset phase (day 7–14) as well as the recovery phase (day 14–30) of disease is also shown. For the onset phase no significant difference was detected, whereas PdpnTG mice recovered significantly better than WT mice (P = 0.0045). Data are representative of at least 4 mice per group and 3 independent experiments. (B) Graphs show time of onset, mean maximum score, and time with a score of 3 or higher for WT mice and PdpnTG mice (line 552). For more information also refer to Table 2. (C) Mononuclear cells were isolated from the CNS of WT and PdpnTG mice (line 552) at the peak of disease and analyzed for expression of PDPN and FOXP3 by flow cytometry. Plots show live CD4+CD11b– T cells only and are representative of more than 3 independent experiments. Numbers represent the percentage of CD4 T cells. (D) Mononuclear cells were isolated from the CNS of WT and PdpnTG mice (line 552) at the peak of disease and counted. Cells were analyzed for expression of FOXP3, IL-17A, IFN-γ, and IL-10 by flow cytometry. Data points represent individual mice. Horizontal bars indicate the mean.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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