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Lpar5 Regulates CD8 T Cell Survival and NK Receptor Expression During the Early Response to LCMV Clone 13

ABSTRACT: Persistent antigen exposure during chronic viral infection and tumor development drives CD8 T cells into an exhausted, hypofunctional state. Understanding the molecular pathways that enforce T cell exhaustion is critical for improving current immunotherapies. Work from our lab described how the bioactive lipid lysophosphatidic acid (LPA) regulates CD8 T cell function through LPA receptor 5 (LPAR5) signaling. Lpar5–/– CD8 T cells also exhibit enhanced tumor clearance in murine models of melanoma. Importantly, significantly elevated levels of LPA have been identified in individuals with different cancers and persistent viral infections such as HIV, HCV, and HBV. To investigate the role of Lpar5 in the differentiation and maintenance of exhausted CD8 T cells, we utilized the LCMV infection model. In response to infection with LCMV Clone 13, but not Armstrong, one quarter of Lpar5–/– animals succumbed to infection, and this was accompanied by an increased frequency of LCMV-specific Lpar5–/– CD8 T cells maintained in a less terminally exhausted state. Using P14 transgenic mice, we demonstrate that Lpar5 acts in a cell-intrinsic and temporal manner to regulate CD8 T cell accumulation and exhaustion programming during Clone 13 infection. The enhanced accumulation of Lpar5–/– P14 cells during the acute phase of Clone 13 infection appears to be regulated by Lpar5-mediated changes in T cell survival and not through trafficking or proliferation. RNA sequencing analyses and surface phenotyping show that Lpar5 likely regulates CD8 T cell exhaustion through modulation of the CD94/NKG2A inhibitory axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE301450 | GEO | 2025/07/06

REPOSITORIES: GEO

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