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Long noncoding RNA regulation of immunity

Nature Immunology volume 27, pages 16–25 (2026)Cite this article

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Abstract

Genes encoding long noncoding RNAs (lncRNAs) are intimately involved in mammalian immunity. Here we review recent knowledge of how lncRNAs regulate immune cell specification and function. Beyond canonical roles in nuclear architecture, chromatin modification and posttranscriptional regulation, lncRNA regulation of metabolic pathways, antigenic extracellular lncRNA ribonucleoprotein complexes and glycosylated noncoding RNAs on the cell surface have emerged as newly recognized regulatory mechanisms. In the immune system, specific lncRNAs control lineage determination during hematopoiesis as well as immune cell activation and function during immune responses, while lncRNA dysregulation is associated with immune-related diseases. In particular, we highlight how a female-specific lncRNA XIST promotes female-biased autoimmunity. Finally, we discuss emerging technologies in high-throughput functional genomics, human genetics, molecular interaction mapping, artificial intelligence and synthetic biology that are accelerating our understanding of lncRNA biology in immunity and beyond.

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Fig. 1: lncRNA regulatory mechanism in immune cells.
Fig. 2: lncRNA regulatory principles in immunity.
Fig. 3: Dual role of XIST in female-biased autoimmunity.
Fig. 4: Emerging technologies for advancing lncRNA biology.

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Acknowledgements

We thank members of the Chang and Yu labs for discussions. Supported by Stanford RNA Medicine Program (to H.Y.C.) and Scleroderma Research Foundation (to H.Y.C. and B.Y.).

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Author notes

  1. Howard Y. Chang

    Present address: Amgen Research, South San Francisco, CA, USA

Authors and Affiliations

  1. Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Bingfei Yu

  2. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Bingfei Yu

  3. Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA

    Bingfei Yu

  4. Departments of Dermatology, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Howard Y. Chang

  5. RNA Medicine Program, Stanford University, Stanford, CA, USA

    Howard Y. Chang

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  1. Bingfei Yu
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  2. Howard Y. Chang
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Correspondence to Bingfei Yu or Howard Y. Chang.

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Competing interests

H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio, Cartography Biosciences and Orbital Therapeutics, and was an advisor of 10x Genomics, Arsenal Bio, Chroma Medicine, Exai Bio and Vida Ventures. H.Y.C. is an employee and stockholder of Amgen as of 16 December 2024. B.Y. has no competing interests.

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Nature Immunology thanks Katherine Fitzgerald, K. Mark Ansel, Xuetao Cao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

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Yu, B., Chang, H.Y. Long noncoding RNA regulation of immunity. Nat Immunol 27, 16–25 (2026). https://doi.org/10.1038/s41590-025-02355-9

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