Marguerie Flavien, Saifi Mohammad A, Geary Benjamin, Barnes David, Jonsson Anna H, Ho I-Cheng
Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Harvard Medical School, Boston, MA 02115.
bioRxiv. 2025 May 7:2025.05.01.651731. doi: 10.1101/2025.05.01.651731.
SIRPG, a primate-specific type 1 transmembrane protein in the Signal Regulatory Protein (SIRP) family, is predominantly expressed in T cells. It contains a short cytoplasmic domain, which does not contain any known signaling motif, and its only known ligand is CD47. Several genetic variations in , including the V263A (rs6043409) polymorphism, linked to increased type 1 diabetes risk, highlight its potential importance. However, its expression and physiological role remain largely unclear due to its absence in rodents. Here, we demonstrate that SIRPG and GzmB exhibit near mutually exclusive expression in resting peripheral CD8+ T cells. We further show that SIRPG serves as a valuable marker for GzmK-expressing CD8+ T cells in peripheral blood and inflamed synovial fluid and that its expression in both CD4+ and CD8+ T cells is upregulated by anti-CD3 stimulation, with further enhancement by the TNFα inhibitor adalimumab, but not certolizumab. While SIRPG ablation minimally affects T cell activation and IFNγ/TNFα production, it impairs the expression of mitosis-regulating genes like and , leading to reduced proliferation, and alters the expression of certain activation-induced surface molecules, including CRTAM. Notably, SIRPG-mediated proliferation and CRTAM expression are cell-autonomous and CD47-independent. Structural and functional analyses reveal that SIRPG-driven proliferation is independent of its extracellular D1 domain, not significantly affected by the V263 variant, but dependent on its cytoplasmic domain. Collectively, our findings offer novel insights into the expression, function, and mechanism of action of SIRPG in T cells.
信号调节蛋白（SIRP）家族中的SIRPG是一种灵长类动物特有的1型跨膜蛋白，主要在T细胞中表达。它包含一个短的细胞质结构域，该结构域不包含任何已知的信号基序，其唯一已知的配体是CD47。SIRPG的几种基因变异，包括与1型糖尿病风险增加相关的V263A（rs6043409）多态性，突出了其潜在的重要性。然而，由于其在啮齿动物中不存在，其表达和生理作用在很大程度上仍不清楚。在这里，我们证明SIRPG和颗粒酶B（GzmB）在静息外周CD8+T细胞中表现出几乎相互排斥的表达。我们进一步表明，SIRPG是外周血和炎症滑膜液中表达颗粒酶K（GzmK）的CD8+T细胞的一个有价值的标志物，并且其在CD4+和CD8+T细胞中的表达通过抗CD3刺激而上调，TNFα抑制剂阿达木单抗可进一步增强，但赛妥珠单抗则不能。虽然SIRPG缺失对T细胞活化和IFNγ/TNFα产生的影响最小，但它会损害有丝分裂调节基因如[具体基因1]和[具体基因2]的表达，导致增殖减少，并改变某些活化诱导的表面分子的表达，包括脊髓灰质炎病毒受体相关分子（CRTAM）。值得注意的是，SIRPG介导的增殖和CRTAM表达是细胞自主的且不依赖于CD47。结构和功能分析表明，SIRPG驱动的增殖独立于其细胞外D1结构域，不受V263变体的显著影响，但依赖于其细胞质结构域。总的来说，我们的研究结果为SIRPG在T细胞中的表达、功能和作用机制提供了新的见解。
