title: 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.forename: Anneli
authors.initials: A
authors.lastname: Peters
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Burkett
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Estelle
authors.initials: E
authors.lastname: Bettelli
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D008231:Lymphopenia / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; C490441:Pdpn protein, mouse; D000098853:Podoplanin