MHC I类分子对TLR触发的天然免疫应答的调控作用及其机制研究

Toll-like receptors (TLRs) are the key pattern recognition receptors utilized by cells of the innate immune system to detect conserved components from a wide variety of pathogens, and play critical roles in the host defense against invading microbial pathogens. Many factors are identified to be essential for the full activation of TLR responses, however, inhibitors of TLRs pathways needs further investigation, as inappropriate activation or overactivation of TLR signaling pathways may result in inflammatory disorders such as septic shock or autoimmune diseases. .Major histocompatibility complex (MHC) class I molecules are expressed on all nucleated cells. In addition to the classical function of antigen presentation, MHC class I molecules can also mediate reserve signal once ligated. Aggregation of MHC class I molecules could activate signal pathways in T cells, B cells, tumor cells or endothelial cells, and elicit different biological functions as cell apoptosis, activation or proliferation. However, up to now, what are the non-classical functions of MHC class I molecules and their reverse signal in myeloid cells or APCs are not elucidated yet. Our recent work showed that intracellular MHC class II molecules could promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Whether and how do MHC class I molecules intersect with innate TLR signal pathways and regulate TLR-triggered innate inflammatory response remain unknown. .In this proposal, we will investigate the role of MHC class I molecules on TLR-triggered innate immune responses and the underlying mechanisms. Our study will contributed to the current understanding of immune regulations in both innate and adaptive immunity, and faciliate the development of effective therapeutic protocol for treating infectious diseases.

TLR在机体的抗感染免疫中起到关键作用，他的活化必须受到精密的调控，以免引发过度的炎症反应导致机体免疫损伤，这也是近年免疫学研究热点。经典的MHC 分子是激发获得性免疫的关键分子，主要发挥抗原递呈作用，然而在天然免疫中的功能未有报道。本研究所已发表的论文证实MHC II类分子可以通过维持btk活化，增强TLR信号传导，而MHC I类分子逆向信号在TLR诱导的炎症反应中的效应仍未有研究。我们的预实验表明MHC I类分子能够抑制TLR配体激发的巨噬细胞炎性因子的分泌，提示可能在TLR信号的调控中发挥一定作用。本研究将利用细菌、病毒感染模型和基因敲除小鼠详细探讨MHC I类分子在天然免疫中的调控作用及其分子机制，将有助于更好的理解机体免疫稳态的维持，为临床相关疾病的诊治提供理论基础。

TLR信号诱导的炎症免疫应答在机体抗感染免疫中发挥重要的功能，应答过强过弱都会对机体产生损伤，因而其调控一直是免疫学的研究热点。MHC I类分子作为经典的抗原递呈分子，主要在启动获得性免疫中发挥作用，在天然免疫中的功能尚不清楚。我们的研究证明了MHC I类分子缺失小鼠的虽然减弱了获得性免疫T细胞的抗感染作用，然而在早期固有免疫应答阶段却可以增强机体的炎症应答，加速病原体清除。通过骨髓重建及巨噬细胞剔除再回输实验，我们证明了是髓系细胞表面的MHC I分子缺失导致了小鼠对TLR应答增强，产生大量炎症因子，从而调节了病原体的清除。MHC I类分子的胞内段在TLR信号活化后可以被Src磷酸化，继而招募Fps激酶，Fps通过磷酸化SHP2，下调TRAF6的泛素化活化，继而降低了NF-kB及下游细胞因子的转录。同时我们还研究了MHC I分子对VSV等RNA病毒感染的调控作用，发现MHC I缺失后巨噬细胞清除病毒能力增强，然而并未伴随I型干扰素的增多。进一步机制研究表明，MHC I分子通过SHP2抑制了干扰素下游p-STAT1的磷酸化活化，抑制干扰素的抗病毒效应，导致病毒扩增增强，从而激发了更多的干扰素产生。本研究揭示了经典的抗原递呈分子MHC I在天然免疫调控中的非经典功能，将有助于更好的理解机体免疫稳态的维持，为临床相关疾病的诊治提供理论基础。