Co-signaling receptors for the T cell receptor (TCR) are important therapeutic targets, with blockade of 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 potential therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which of TIM-3's several proposed regulatory ligands is/are relevant for signaling is unclear, and different studies have reported TIM-3 as a co-inhibitory or co-stimulatory receptor in T cells. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following TCR stimulation in Jurkat cells, and that this activity is regulated by binding to phosphatidylserine (PS). 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 clarify the importance of PS as a functional TIM-3 ligand, and may inform the future exploitation of TIM-3 as a therapeutic target.

中文翻译：

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磷脂酰丝氨酸结合直接调节 TIM-3 功能

T 细胞受体 (TCR) 的共信号受体是重要的治疗靶点，阻断共抑制受体（如 PD-1）现在是免疫肿瘤学的核心。推进额外的治疗性免疫调节方法需要了解其他共信号受体的配体调节。一个鲜为人知的潜在治疗靶点是 TIM-3（T 细胞免疫球蛋白和含有粘蛋白结构域的 3）。TIM-3 的几种提议的调节配体中的哪一个与信号传导相关尚不清楚，不同的研究报告 TIM-3 作为 T 细胞中的共抑制或共刺激受体。在这里，我们表明 TIM-3 在 Jurkat 细胞中的 TCR 刺激后促进 NF-κB 信号传导和 IL-2 分泌，并且该活性通过与磷脂酰丝氨酸 (PS) 结合进行调节。TIM-3 信号由在培养的 Jurkat 细胞中组成性暴露的 PS 刺激，并且可以通过突变 PS 结合位点或用抗体封闭该位点来阻断。我们还发现 TIM-3 信号改变了 CD28 磷酸化。我们的研究结果阐明了 PS 作为功能性 TIM-3 配体的重要性，并可能为 TIM-3 作为治疗靶点的未来开发提供信息。