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

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 1

PDPN-deficient mice show exaggerated T cell responses.

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PDPN-deficient mice show exaggerated T cell responses. (A) Lungs and int...
(A) Lungs and intestines were harvested from PDPN-deficient mice and their WT littermates. Sections of the formalin-fixed and paraffin-embedded tissues were stained with hematoxylin and eosin. Both Pdpn–/– lung and small intestine show lymphocytic infiltrates (dark blue, arrows). Sections of lung and intestine were also analyzed for the presence of T cells (CD3, dark brown) by immunohistochemistry (right panels). Scale bar: 50 μm. For more information refer to Supplemental Table 1. (B) The number of small, medium, and large infiltrates in the small intestines of PDPN-deficient mice (n = 4) and their WT or heterozygous littermates (n = 4) was quantified. (C) Sorted naive T cells from PDPN-deficient mice and their WT littermates were stimulated in vitro with different concentrations of anti-CD3 in the presence of irradiated APCs for 72 hours. Proliferation was measured by thymidine incorporation in the last 18 hours. Data shown are representative of 3 or more independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001.