Abstract
Transposable elements (TEs) are mobile repetitive nucleic acid sequences that have been incorporated into the genome through spontaneous integration, accounting for almost 50% of human DNA. Even though most TEs are no longer mobile today, studies have demonstrated that they have important roles in different biological processes, such as ageing, embryonic development, and cancer. TEs influence these processes through various mechanisms, including active transposition of TEs contributing to ongoing evolution, transposon transcription generating RNA or protein, and by influencing gene regulation as enhancers. However, how TEs interact with the immune system remains a largely unexplored field. In this Perspective, we describe how TEs might influence different aspects of the immune system, such as innate immune responses, T cell activation and differentiation, and tissue adaptation. Furthermore, TEs can serve as a source of neoantigens for T cells in antitumour immunity. We suggest that TE biology is an important emerging field of immunology and discuss the potential to harness the TE network therapeutically, for example, to improve immunotherapies for cancer and autoimmune and inflammatory diseases.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) Projektnummer 324392634-TRR 221 to M.F.
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L.S., P.S. and M.F. conceptualized the review. L.S., P.S. and M.F. wrote the main body. All authors contributed to editing of the manuscript and providing references. All authors approved the submitted version of the article.
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Glossary
- CRISPR activation
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(CRISPRa). A modified CRISPR–Cas9 system using a deactivated Cas9 (dCas9) fused to a transcriptional activator to enhance the expression of genes without affecting the DNA sequence.
- CRISPR–Cas9
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A genetic engineering system that induces double-stranded breaks in a sequence-specific manner by duplexing a Cas9 nuclease with a guide RNA. Genetic alterations are induced through non-homologous end joining and homology-directed repair.
- CRISPR–Cas-derived base editors
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A catalytically impaired CRISPR–Cas system that induces targeted point mutations without double-stranded DNA breaks.
- CRISPR interference
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(CRISPRi). A modified CRISPR–Cas9 system using a deactivated Cas9 (dCas9) fused to a repressor construct that can be used to silence the transcription of genes without altering the DNA sequence.
- Domestication
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An evolutionary process during which foreign material is integrated into the genome to fulfil a function that is beneficial to the host organism, for instance, the integration of transposons into the genome to form the RAG genes.
- Endogenous retroviruses
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(ERVs). Retrotransposons of the long-terminal repeat (LTR) subclass derived from retroviruses.
- Host–transposase fusion (HTF) genes or proteins
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Genes or proteins that are comprised partially of host and partially of transposon material. Many transcription factors are HTF genes, combining transposable element-derived DNA-binding domains with host regulatory domains.
- JETs
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Non-canonical splice junctions involving exons and transposable elements (junctions between exons and transposable elements).
- Lancelets
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A group of primitive chordates; a frequently used animal model system used to study evolution.
- LINE-1
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Long interspersed nuclear element-1 also known as L1, both a retrotransposon and a group of retrotransposons of the non-long-terminal repeat (LTR) family and LINE subfamily.
- Metastable epialleles
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Loci that show systemic variable DNA methylation among individuals without underlying genetic differences.
- MHC class I-associated peptides
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(MAPs). Peptides that can be presented by MHC class I molecules and recognized by CD8 T cells.
- Micro-evolution
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Small-scale evolutionary changes that occur over a relatively short period of time. An example of micro-evolution is the development of antibiotic resistance in bacteria.
- TE exonization
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The process of incorporating transposable elements (TEs) from non-coding regions, predominantly introns, into new exons, using splicing signal sequences.
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Schmidleithner, L., Stüve, P. & Feuerer, M. Transposable elements as instructors of the immune system. Nat Rev Immunol 25, 696–706 (2025). https://doi.org/10.1038/s41577-025-01172-3
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DOI: https://doi.org/10.1038/s41577-025-01172-3
