Podoplanin negatively regulates CD4+ effector T cell responses
Anneli Peters, Patrick R. Burkett, Raymond A. Sobel, Christopher D. Buckley, Steve P. Watson, Estelle Bettelli, Vijay K. Kuchroo
Anneli Peters, Patrick R. Burkett, Raymond A. Sobel, Christopher D. Buckley, Steve P. Watson, Estelle Bettelli, Vijay K. Kuchroo
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Research Article Immunology

Podoplanin negatively regulates CD4+ effector T cell responses

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 6

Natural PDPN+ T effector cells in the CNS show an inhibited phenotype.

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Natural PDPN+ T effector cells in the CNS show an inhibited phenotype. (...
(A) WT mice were immunized with MOG/CFA for the development of EAE. Expression of PDPN on CD4 T cells isolated from spleens (SP) and lymph nodes 8 days after immunization and from the CNS either at the onset of disease or during recovery was determined by flow cytometry. Numbers represent the percentage of CD4 T cells. (B–D) Foxp3.GFP-KI mice were immunized with MOG/CFA for the development of EAE. At the peak of disease, infiltrating cells were isolated from the CNS and Foxp3.GFP–CD11b–CD4+PDPN+ and Foxp3.GFP–CD11b–CD4+PDPN– T cells were isolated by FACS sorting. (B) mRNA gene expression profiles were generated from both populations using NanoString technology. Graphs show selected genes that were consistently downregulated or upregulated in PDPN+ T effectors compared with PDPN– T effectors in 3 independent experiments. (C) mRNA was isolated from both populations, and the expression patterns of Il7ra and Bcl2 were confirmed by quantitative PCR. Graphs shown are representative of 2 independent experiments. (D) PDPN+ and PDPN– T effector cells isolated from the CNS were analyzed for expression of PD-1 and TIM-3 by flow cytometry, and the percentage of TIM-3+PD-1+ T cells among each group is shown. (E) WT CD4 T cells were stimulated with plate-bound anti-CD3 and anti-CD28 Abs and differentiated in the presence of no cytokine (Th0), IL-6 and TGF-β, or IL-1β, IL-6, and IL-23. After 4 days, cultures were analyzed for expression of PDPN by flow cytometry. Data are representative of more than 3 independent experiments.