Bat3通过mTORC2/Tim-3调控Tregs在肝移植免疫耐受中的作用机制研究

Regulatory T cells (Tregs) are the key cells to induce transplant tolerance. How to use Tregs more efficiently and stably to induce transplant tolerance is still the hot topic in the field of liver transplantation. Previous studies have shown that Tim-3 could promote Foxp3 expression and enhance Tregs function, but it also could induce cell exhaustion. In preliminary experiments we showed that inhibition of Bat3 could stably promote Tim-3 expression, and Bat3 could inhibit mTORC2 function by specifically binding to Rictor. Therefore, we hypothesized that inhibition of Bat3 could enhance Tregs function by promoting Tim-3 expression through mTORC2, and induce liver transplant tolerance. In the current study, we aim to establish the liver transplant model using Bat3 conditional knockout mice, observe allograft survival, analyze the infiltrating Tregs function and sort them out for RNA-Sequencing, test the effect of Bat3 on Tregs differentiation in vitro and in adoptive transfer model in vivo, verify whether Bat3 regulates Tim-3 expression through mTORC2 in Tregs and whether the function of Bat3 on Tregs is dependent on Tim-3 by using Bat3 Tim-3 double conditional knockout mice, and finally exploit the potential of Bat3ko Tregs in the induction of liver transplant tolerance in patients. The project will help to understand the mechanism of transplant tolerance, and provide a scientific basis for the induction of liver transplant tolerance.

调节性T细胞（Tregs）是诱导移植免疫耐受的关键细胞。如何更高效、稳定地使用Tregs诱导免疫耐受是肝移植领域的研究热点。研究发现，Tim-3可增强Tregs的表达和功能，但易发生细胞耗竭。预实验结果显示，抑制Bat3可稳定诱导Tim-3表达，而Bat3能够特异性与Rictor结合，从而抑制mTORC2功能。由此我们推测，阻断Bat3能够通过mTORC2稳定诱导Tim-3表达，增强Tregs功能，进而诱导持久的肝移植免疫耐受。本课题拟采用Bat3敲除小鼠建立肝移植模型，观察移植物存活情况，并从体内、外实验检测Bat3对Tregs的影响；进而在分子、细胞、动物水平上检测阻断Bat3是否通过mTORC2促进Tim-3表达，增强Tregs功能；最后在临床上验证Bat3敲除Tregs诱导肝移植持久免疫耐受的可行性。本课题将为诱导肝移植免疫耐受提供科学依据，为特异性诱导持久的免疫耐受提供新的思路。

调节性T细胞（Tregs）是诱导移植免疫耐受的关键细胞。研究发现，Tim-3可增强Tregs的表达和功能，但易发生细胞耗竭。在本项目的研究中，我们将通过阻断Bat3增强Tim-3表达在诱导肝移植免疫耐受中的作用，并通过一系列体内外实验,研究Bat3与Tim-3之间的关系及其在Tregs中的作用，以及其在肝移植免疫耐受的细胞免疫学机制。我们的研究显示：在Tregs中特异性敲除Bat3的小鼠中，阻断Bat3能增强Foxp3及Tim-3的表达，延长小鼠移植物的长期存活，在机制上，我们发现Bat3能与Rictor结合，增强mTORC2的功能及其下游p-Akt的表达，增强Tregs功能，在临床水平上，我们发现Tregs中Bat3的表达与移植排异密切相关。此项研究能够为特异性诱导持久的免疫耐受提供理论依据。目前本项目已发表4篇研究论文。

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