Li Shang, Zhang Peng, Li Ao, Bao Jiayu, Pan Zhiqiang, Jie Ying
Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China.
Transplantation. 2023 Feb 1;107(2):372-381. doi: 10.1097/TP.0000000000004257. Epub 2023 Jan 26.
Reduction of graft rejection remains key issue for supporting long-term graft retention after corneal transplantation. The relevance of Treg in reduction of corneal allografts rejection has been demonstrated. It has been recently reported that in addition to Foxp3, Helios is also considered to be a marker of activated Treg. Helios + Foxp3 + Treg are considered to be the true immunosuppressive Treg. TIGIT is an immunosuppressive costimulatory molecule that was found to be highly expressed on the surface of Helios + Foxp3 + Treg.
In this study, we aimed to explore whether supplementing TIGIT would result in an expansion and activation of Helios + Foxp3 + Treg thus to mediate an immune tolerance following corneal transplantation by administering topically and systemically TIGIT-Fc treatment in murine models.
TIGIT-Fc treatment significantly improved the survival of corneal allograft compared with the control group. TIGIT-Fc treatment increased TIGIT/CD226 expression, the proportion of Helios + Foxp3 + Treg cells and an enhanced ex vivo suppressive effect from peripheral lymph nodes isolated Treg cells. Furthermore, the expression of Helios in corneal grafts was upregulated, whereas expression of CD226 and production of aqueous interferon-γ and VEGF were reduced by TIGIT-Fc treatment.
TIGIT-Fc treatment could specifically upregulate Helios + Foxp3 + Treg-mediated immune response after allogeneic corneal transplantation via TIGIT/CD226-CD155 pathway which improves the survival of allografts.
减少移植物排斥反应仍然是角膜移植后支持长期移植物留存的关键问题。已证实调节性T细胞（Treg）在减少角膜同种异体移植排斥反应中的相关性。最近有报道称，除了叉头框蛋白3（Foxp3）外，太阳神蛋白（Helios）也被认为是活化Treg的标志物。Helios + Foxp3 + Treg被认为是真正具有免疫抑制作用的Treg。T细胞免疫球蛋白和免疫酪氨酸抑制基序（TIGIT）是一种免疫抑制性共刺激分子，被发现高表达于Helios + Foxp3 + Treg的表面。
在本研究中，我们旨在通过在小鼠模型中局部和全身给予TIGIT-Fc治疗，探索补充TIGIT是否会导致Helios + Foxp3 + Treg的扩增和活化，从而介导角膜移植后的免疫耐受。
与对照组相比，TIGIT-Fc治疗显著提高了角膜同种异体移植的存活率。TIGIT-Fc治疗增加了TIGIT/CD226的表达、Helios + Foxp3 + Treg细胞的比例，并增强了从外周淋巴结分离的Treg细胞的体外抑制作用。此外，TIGIT-Fc治疗上调了角膜移植物中Helios的表达，但降低了CD226的表达以及房水中干扰素-γ和血管内皮生长因子（VEGF）的产生。
TIGIT-Fc治疗可通过TIGIT/CD226-CD-155途径特异性上调同种异体角膜移植后Helios + Foxp3 + Treg介导的免疫反应，从而提高移植物的存活率。
