脓毒症是ICU的重要致死因素，T细胞失能是脓毒症免疫抑制、病情进展的重要原因。失能T细胞中存在Ca2+内流、NFAT核转位以及TGF-β信号通路激活。研究证明整合素αv（ITGAV）参与免疫抑制过程，但其机制仍未明确。申请人研究发现ITGAV可激活TGF-β信号通路(Oncogene. 2017；Cell Death Dis. 2018)。前期研究发现ITGAV在脓毒症患者CD4+T细胞中高表达，且TGF-β促进ITGAV被ɣ-分泌酶切割并入核。基于此我们提出假说：ɣ-分泌酶可对ITGAV胞内段切割形成剪切体，致CD4+T细胞Ca2+内流及NFAT核转位，促使T细胞失能，进而导致脓毒症进展。本课题拟通过RNA-seq探索ITGAV调控T细胞失能的分子机制，利用体内外细胞-分子生物学实验以及临床资料阐明ITGAV的剪切体在脓毒症的发展重的作用机制，为脓毒症免疫治疗提供新的理论基础。

Sepsis is an important lethal factor in ICU. T cell insufficiency is an important cause of immunosuppression and progression of sepsis. Ca2+ influx, NFAT nuclear translocation and activation of TGF-β signaling pathway are present in incapacitated T cells. Studies have shown that integrin αv (ITGAV) is involved in the process of immunosuppression, but the mechanism remains unclear. The applicant's preliminary study has found that ITGAV can activate the TGF signaling pathway (Oncogene. 2017; Cell Death Dis. 2018). Previous studies have found that ITGAV is highly expressed in CD4+ T cells of septic patients, and TGFβ promotes ITGAV cleavage into the nucleus by ɣ-secretase. Based on this, we propose a hypothesis: ɣ-secretase can cleave the intracellular segment of ITGAV, causing Ca2+ influx and NFAT nuclear translocation in CD4+ T cells, which induces the dysfunction of T cells and leads to the progression of sepsis. This study intends to explore the molecular mechanism of T cell inactivation regulated by ITGAV through the technology of RNA-seq, using both in vitro and in vivo cell-molecular biology experiments and the clinical data to elucidate the mechanism that how ITGAV spliceosome develop the sepsis, which can provides a new theoretical basis for the immunotherapy of sepsis.