W156 - Expression and CD47-Independent Function of SIRPG: A Primate T Cell-Specific Gene

Abstract Text: SIRPG is an immunoglobulin-like transmembrane protein expressed almost exclusively in primate T cells. Genetic variations in SIRPG have been linked to increased risk of type 1 diabetes and its level in tumor infiltrating lymphocytes is prognostic in several cancers. Its only known ligand is CD47, however, its function and how its expression is regulated remain poorly understood due to its absence in rodents. Here, we show that SIRPG expression is downregulated in effector T cells and is almost mutually exclusive with Granzyme B expression in resting peripheral T cells. Its expression is induced by anti-CD3 stimulation and further enhanced by the TNF-α inhibitor adalimumab but not certolizumab. Ablation of SIRPG has little impact on the activation and production of IFNg or TNFa of T cells but lead to impaired expression of several mitosis-regulating genes, including UBE2C and CDK1, resulting in less robust proliferation, and a subset of activation-induced co-receptors, such as CRTAM, SEMA4a, TNFRSF9, and TNFRSF18. Interestingly, SIRPG and its down-stream genes are enriched in a unique cluster of melanoma-infiltrating exhausted CD8 T cells expressing a high level of cell cycle genes. Mechanistically, the SIRPG-mediated proliferation and expression of CRTAM is cell autonomous and independent of CD47. Structural and functional analyses will be carried out to investigate the role of its extracellular and cytoplasmic domains. Collectively, our findings provide novel insights into the regulation, function, and mechanism of action of SIRPG in T cells, with potential implications for modulating the T cell response in various human diseases.