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标题：Developmentally distinct CD4 + T reg lineages shape the CD8 + T cell response to acute Listeria infection
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作者：Joseph S. Dolina ; Joey Lee ; Eugene L. Moore 等
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：2022
卷号：119
期号：10
DOI：10.1073/pnas.2113329119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance The CD4 + T reg response following acute Listeria infection is heterogeneous and deploys two distinct modes of suppression coinciding with initial pathogen exposure and resolution of infection. This bimodal suppression of CD8 + T cells during priming and contraction is mediated by separate T reg lineages. These findings make a significant contribution to our understanding of the functional plasticity inherent within T reg s, which allows these cells to serve as a sensitive and dynamic cellular rheostat for the immune system to prevent autoimmune pathology in the face of inflammation attendant to acute infection, enable expansion of the pathogen-specific response needed to control the infection, and reestablish immune homeostasis after the threat has been contained. CD4 + regulatory T cells (T reg s) must prevent immunopathology by cytotoxic CD8 + T lymphocytes (CTLs) responding to acute infection and restore immune homeostasis following pathogen clearance, yet little is known about the specific populations or mechanisms governing these discrete events. We found that acute Listeria monocytogenes ( L. monocytogenes) infection produces a phenotypically and functionally complex T reg response comprising two separate suppressor cell subpopulations, with an early T reg peak occurring at 24 h postinfection and a later peak arising by day 7. The first wave of T reg s suppress primary CTL expansion via a contact-independent mechanism involving CD73-derived adenosine (Ado) production from extracellular adenosine monophosphate (5′-AMP), while the second originates from different precursors and acts throughout the contraction phase via contact-dependent gap junction transfer of 3′,5′-cyclic adenosine monophosphate (cAMP)—both potent inhibitors of T cell proliferation. We speculate that the early activation of CD73 on T reg s is enhanced in inflamed tissues due to high purine release from apoptotic cells, whereas late-phase gap junction–dependent T reg s rely more on cell number and less on tissue inflammation. This study importantly reveals that CTL priming and contraction phases are separately fine-tuned by developmentally distinct T reg lineages during an acute infection.
关键词：enFoxP3+T regulatory cellCD73gap junctioncyclic AMPListeria monocytogenes