Intrinsic Alteration of Differentiation and Glycolysis in T Lymphocytes Immediately After TCR Activation Through PSGL-1 Signaling

• Published in: The Journal of immunology (1950) 2019-05, Vol.202 (1_Supplement), p.117-117.25
• Main Authors: Hope, Jennifer L, Otero, Dennis, de Jong, Petrus, Ma, Jiadai, Henriquez, Monique, Powis, Garth, Bradley, Linda
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.117.25

P-selectin glycoprotein ligand-1 (PSGL-1) is an adhesion molecule expressed on the surface of naïve, effector, and memory CD4+ and CD8+ T cells. We identified PSGL-1 to be an immune checkpoint inhibitor as antibody-mediated ligation of PSGL-1 promotes T cell exhaustion and deletion of PSGL-1 prevents chronic viral infection and inhibits tumor. To investigate the role of PSGL-1 signaling in the development of T cell responses, we assessed the differentiation state, expansion capacity, and glycolytic profile of PSGL-1-deficient T cells. PSGL-1+/− OT-II CD4+ T cells demonstrated increased skewing towards IL-17A+ T cells compared to wild-type OT-II CD4+ T cells under TH17 conditions, and reduced IFNg+ cells under both TH0 and TH1 conditions. In a B16-OVA tumor model, we observed increased IL-13+ CD4+ T cells among the intratumoral T cell compartment in PSGL-1−/− mice. In vitro activation with a sub-optimal dose of αCD3 of PSGL-1−/− OT-II CD4+ T cells demonstrated increased expansion and expression of CD25 compared to wild-type OT-II CD4+ T cells. Further, adoptively transferred in vitro-activated PSGL-1−/− CD4+ T cells demonstrated greater expansion in vivo upon adoptive transfer into RAG−/− host mice. Using the Seahorse glycolysis stress test, we identified that both CD4+ and CD8+ PSGL-1−/− T cells demonstrate increased glycolysis after 72 hours of in vitro activation compared to wild-type T cells. Further, in situ activation of PSGL-1−/− CD8+ T cells demonstrates that at both sub-optimal and optimal levels of αCD3 stimulation, PSGL-1−/− CD8+T cells have increased glycolysis and increased glycolytic capacity. Taken together, these data show that PSGL-1 signaling has an intrinsic and immediate role in the development of T cell responses.