RAG suppresses group 2 innate lymphoid cells

RAG suppresses group 2 innate lymphoid cells

Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence...

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Main Authors: Aaron M Ver Heul, Madison Mack, Lydia Zamidar, Masato Tamari, Ting-Lin Yang, Anna M Trier, Do-Hyun Kim, Hannah Janzen-Meza, Steven J Van Dyken, Chyi-Song Hsieh, Jenny M Karo, Joseph C Sun, Brian S Kim
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2025-05-01
Series:eLife
Subjects:
innate lymphoid cell
RAG
inflammation
allergic
dermatitis
atopic
Online Access:https://elifesciences.org/articles/98287
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Summary:Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Furthermore, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.
ISSN:2050-084X

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