LPAR5-Mediated Regulation of CD8 T Cell Immunity During Chronic Viral Infections

• Published in: The Journal of immunology (1950) 2023-05, Vol.210 (1_Supplement), p.59-59.28
• Main Authors: D’Antonio, Marc, Ware, Brian C., Turner, Jacqueline A., Davenport, Bennett J., Morrison, Thomas E., Torres, Raul M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.59.28

Persistent viral infections such as Human Immunodeficiency Virus (HIV), Hepatitis B and C Viruses (HBV & HCV), and Epstein Barr Virus (EBV) result in high mortality rates, tremendous healthcare costs, and limit global life expectancies. Paramount to establishing and maintaining chronic infections, viruses must evade or suppress T cell-mediated immunity, often through promoting the generation of dysfunctional or “exhausted” CD8 T cells. Although there are considerable research efforts investigating mechanisms of T cell exhaustion, further work is necessary to identify and characterize therapeutically targetable regulators of exhaustion programming. Work from our lab has focused on the ability of the bioactive lipid, lysophosphatidic acid (LPA), to regulate CD8 T cell function through LPA receptor 5 (LPAR5) signaling. Importantly, significantly elevated levels of LPA have been identified in chronic viral infections and cancers. We previously demonstrated that activation of LPAR5 on CD8 T cells during TCR engagement suppresses downstream signaling events. Since TCR-induced transcriptional networks regulate T cell exhaustion programming, we hypothesize that LPA-mediated changes in gene expression during chronic infections promotes the generation of dysfunctional CD8 T cells. To investigate the role of LPA in the differentiation of exhausted CD8 T cells, we utilized the LCMV Clone 13 infection model. We postulate that the elevated levels of LPA identified in persistent infections and our initial findings investigating LPAR5 signaling in CD8 T cells provide strong a rationale to evaluate LPA signaling as a previously unexplored pathway by which chronic viruses promote T cell exhaustion to establish and maintain persistence. RO1AI143261-02 T32-AI07405