Halpert Matthew M, Konduri Vanaja, Liang Dan, Vazquez-Perez Jonathan, Hofferek Colby J, Weldon Scott A, Baig Yunyu, Vedula Indira, Levitt Jonathan M, Decker William K
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
FASEB J. 2020 Jun;34(6):8082-8101. doi: 10.1096/fj.201903002R. Epub 2020 Apr 16.
Mammalian immune responses are initiated by "danger" signals--immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen-associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel "PAMP" that is not a molecular structure but an antigenic pattern. This pattern--the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II--strongly induces T 1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl-tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T-helper (T ) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell-mediated immunity.
哺乳动物的免疫反应由“危险”信号引发，即被称为病原体相关分子模式（PAMP）的不变分子结构。当被固定的、种系编码的受体检测到时，病原体相关分子模式（PAMP）随后会根据PAMP的特性和定位来决定下游适应性反应的极化方向。在此，我们报告了一种全新“PAMP”的存在，它并非分子结构，而是一种抗原模式。这种模式——与树突状细胞（DC）主要组织相容性复合体（MHC）I类和II类结合的具有100%序列同一性延伸的肽表位的发生率——强烈诱导T1免疫极化和细胞免疫反应的激活。这种PAMP存在的内在因素是同时存在一种分子传感器复合体，它能够扫描和比较结合的I类和II类肽的氨基酸序列同一性。我们提供了大量证据，表明多酶氨酰-tRNA合成酶（mARS）复合体及其AIMp1结构成分是该复合体的关键组成部分。这些结果证明了一种全新的机制，通过该机制可控制辅助性T细胞（Th）极化，并为旨在激发细胞介导免疫的疫苗接种策略设计提供关键信息。
