期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2017460118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The ability of immune cells to distinguish self tissue from nonself pathogens is a key characteristic of immunity, allowing responses to be targeted against invading pathogens while protecting against self-directed immune damage. The recognition of nonself by innate immune cells has been extensively characterized, but the mechanisms that allow for self recognition and self-tolerance remain largely unexplored. Here, we uncover a self-tolerance system in
Drosophila that relies on the N-glycosylation of extracellular matrix proteins: immune activity is restrained by recognition of a self signal and proceeds when encountering self tissues missing the self signal. This allows the host to recognize and protect self tissues, destroy aberrant tissue, and, perhaps, respond to pathogens that evade nonself recognition systems.
In order to respond to infection, hosts must distinguish pathogens from their own tissues. This allows for the precise targeting of immune responses against pathogens and also ensures self-tolerance, the ability of the host to protect self tissues from immune damage. One way to maintain self-tolerance is to evolve a self signal and suppress any immune response directed at tissues that carry this signal. Here, we characterize the
Drosophila tuSz
1
mutant strain, which mounts an aberrant immune response against its own fat body. We demonstrate that this autoimmunity is the result of two mutations: 1) a mutation in the
GCS1 gene that disrupts N-glycosylation of extracellular matrix proteins covering the fat body, and 2) a mutation in the
Drosophila Janus Kinase ortholog that causes precocious activation of hemocytes. Our data indicate that N-glycans attached to extracellular matrix proteins serve as a self signal and that activated hemocytes attack tissues lacking this signal. The simplicity of this invertebrate self-recognition system and the ubiquity of its constituent parts suggests it may have functional homologs across animals.
