TY - JOUR T1 - Phosphatidylserine binding regulates TIM-3 effects on T cell receptor signaling JF - bioRxiv DO - 10.1101/2021.05.07.443190 SP - 2021.05.07.443190 AU - Courtney M. Smith AU - Alice Li AU - Nithya Krishnamurthy AU - Mark A. Lemmon Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/08/2021.05.07.443190.abstract N2 - Co-signaling receptors for the T cell receptor are important therapeutic targets, with blocking co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which ligands are relevant for TIM-3 signaling is unclear, and different studies have reported it as co-inhibitory or co-stimulatory. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following T cell receptor stimulation in Jurkat cells, and is regulated by phosphatidylserine (PS) binding. TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings help clarify conflicting literature results with TIM-3, and inform its exploitation as a therapeutic target.Competing Interest StatementThe authors have declared no competing interest. ER -