MiR-29a/b Suppresses CD8⁺ T Cell Effector Function and Intestinal Inflammation

Abstract

The role of CD8⁺ T cells in the pathogenesis of ulcerative colitis (UC) remains unclear. Similarly, the posttranscriptional regulation of the highly heterogenic CD8⁺ T cell populations and their effector function in IBD also remains poorly understood. Here, we find that miR-29a and -29b (miR-29a/b) regulate T cell fate, and their expression is higher near damaged colon tissue in patients with IBD compared to controls. In mice, we find that miR-29a/b suppresses the differentiation of CD8⁺ T cells and the secretion of pro-inflammatory and chemotactic factors during severe colitis by inhibiting transcriptional pathways, including those involving the T cell receptor and JAK-STAT signaling. Furthermore, we identify Ifng, an inflammatory factor that drives immune response and the reshaping of CD8⁺ T cell fate, as a potential target of the miRNAs. Finally, we show that delivery of miR-29 mimics to the colon of mice is sufficient to alleviate DSS-induced inflammation. Together, these data show that miR-29 plays an important role in suppressing T cell overactivation during inflammatory diseases.

Keywords

CD8⁺ T cell / differentiation / Ifng-JAK-STAT / miR-29a/b / ulcerative colitis

References

[1] D. H. Kim and J. H. Cheon, “Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies,” Immune Network 17 (2017): 25-40.

[2] A. Kołodziejska-Sawerska, A. Rychlik, A. Depta, M. Wdowiak, M. Nowicki, and M. Kander, “Cytokines in Canine Inflammatory Bowel Disease,” Polish Journal of Veterinary Sciences 16 (2013): 165-171.

[3] C. B. Larmonier, K. W. Shehab, F. K. Ghishan, and P. R. Kiela, “T Lymphocyte Dynamics in Inflammatory Bowel Diseases: Role of the Microbiome,” BioMed Research International 2015 (2015): 1-9, https://doi.org/10.1155/2015/504638.

[4] J. K. Whitmire, J. T. Tan, and J. L. Whitton, “Interferon-γ Acts Directly on CD8⁺ T Cells to Increase Their Abundance During Virus Infection,” Journal of Experimental Medicine 201 (2005): 1053-1059.

[5] Y. Liu, Q. Lan, L. Lu, et al., “Phenotypic and Functional Characteristic of a Newly Identified CD8⁺Foxp3⁻CD103⁺ Regulatory T Cells,” Journal of Molecular Cell Biology 6 (2014): 81-92.

[6] H. Rabe, M. Malmquist, C. Barkman, et al., “Distinct Patterns of Naive, Activated and Memory T and B Cells in Blood of Patients With Ulcerative Colitis or Crohn's Disease,” Clinical and Experimental Immunology 197 (2019): 111-129.

[7] H. W. Mittrücker, A. Visekruna, and M. Huber, “Heterogeneity in the Differentiation and Function of CD8⁺ T Cells,” Archivum Immunologiae Et Therapiae Experimentalis 62 (2014): 449-458.

[8] D. Corridoni, T. Chapman, A. Antanaviciute, J. Satsangi, and A. Simmons, “Inflammatory Bowel Disease Through the Lens of Single-Cell RNA-seq Technologies,” Inflammatory Bowel Diseases 26 (2020): 1658-1668.

[9] M. St Paul and P. S. Ohashi, “The Roles of CD8⁺ T Cell Subsets in Antitumor Immunity,” Trends in Cell Biology 30 (2020): 695-704.

[10] B. S. Boland, Z. He, M. S. Tsai, et al., “Heterogeneity and Clonal Relationships of Adaptive Immune Cells in Ulcerative Colitis Revealed by Single-Cell Analyses,” Science Immunology 5 (2020): eabb4432, https://doi.org/10.1126/SCIIMMUNOL.ABB4432.

[11] M. Gasparetto, F. Payne, K. Nayak, et al., “Transcription and DNA Methylation Patterns of Blood-Derived CD8⁺ T Cells Are Associated With Age and Inflammatory Bowel Disease But Do Not Predict Prognosis,” Gastroenterology 160 (2021): 232-244.e7.

[12] Y. H. Lin, H. G. Duong, A. E. Limary, et al., “Small Intestine and Colon Tissue-Resident Memory CD8⁺ T Cells Exhibit Molecular Heterogeneity and Differential Dependence on Eomes,” Immunity 56 (2023): 207-223.e8.

[13] K. Fisher and J. Lin, “MicroRNA in Inflammatory Bowel Disease: Translational Research and Clinical Implication,” World Journal of Gastroenterology 21 (2015): 12274-12282.

[14] R. M. O'Connell, D. S. Rao, A. A. Chaudhuri, and D. Baltimore, “Physiological and Pathological Roles for microRNAs in the Immune System,” Nature Reviews Immunology 10 (2010): 111-122.

[15] T. Wu, A. Wieland, K. Araki, et al., “Temporal Expression of microRNA Cluster miR-17-92 Regulates Effector and Memory CD8⁺ T-Cell Differentiation,” Proceedings National Academy of Science of the United States of America 109 (2012): 9965-9970.

[16] D. T. Gracias, E. Stelekati, J. L. Hope, et al., “The microRNA miR-155 Controls CD8⁺ T Cell Responses by Regulating Interferon Signaling,” Nature Immunology 14 (2013): 593-602.

[17] N. Liu, X. Wang, C. J. Steer, and G. Song, “MicroRNA-206 Promotes the Recruitment of CD8⁺ T Cells by Driving M1 Polarisation of Kupffer Cells,” Gut 71 (2022): 1642-1655.

[18] A. C. Wells, E. L. Pobezinskaya, and L. A. Pobezinsky, “Non-Coding RNAs in CD8 T Cell Biology,” Molecular Immunology 120 (2020): 67-73.

[19] K. J. Yee Mon, H. Zhu, C. W. P. Daly, et al., “MicroRNA-29 Specifies Age-Related Differences in the CD8⁺ T Cell Immune Response,” Cell reports 37 (2021): 109969, https://doi.org/10.1016/j.celrep.2021.109969.

[20] E. Stelekati, Z. Cai, S. Manne, et al., “MicroRNA-29a Attenuates CD8 T Cell Exhaustion and Induces Memory-Like CD8 T Cells During Chronic Infection,” Proceedings National Academy of Science of the United States of America 119 (2022): e2106083119.

[21] E. M. Wissink, N. L. Smith, R. Spektor, B. D. Rudd, and A. Grimson, “MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8⁺ T Cells,” Genetics 201 (2015): 1017-1030.

[22] S. Dey, L. M. Udari, P. RiveraHernandez, et al., “Loss of miR-29a/b1 Promotes Inflammation and Fibrosis in Acute Pancreatitis,” Journal of Clinical Investigation Insight 6 (2021): e149539, https://doi.org/10.1172/jci.insight.149539.

[23] F. Ma, S. Xu, X. Liu, et al., “The microRNA miR-29 Controls Innate and Adaptive Immune Responses to Intracellular Bacterial Infection by Targeting Interferon-γ,” Nature Immunology 12 (2011): 861-869.

[24] O. Brain, B. M. J. Owens, T. Pichulik, et al., “The Intracellular Sensor NOD2 Induces MicroRNA-29 Expression in Human Dendritic Cells to Limit IL-23 Release,” Immunity 39 (2013): 521-536.

[25] Y. Lin, Y. Lu, Z. Huang, et al., “Dietary Exosome-Like Nanoparticles: An Updated Review on Their Pharmacological and Drug Delivery Applications,” Molecular Nutrition & Food Research 66 (2022): e2200142.

[26] A. Kappeler and C. Mueller, “The Role of Activated Cytotoxic T Cells in Inflammatory Bowel Disease,” Histology and Histopathology 15 (2000): 167-172.

[27] D. F. Steiner, M. F. Thomas, J. K. Hu, et al., “MicroRNA-29 Regulates T-Box Transcription Factors and Interferon-γ Production in Helper T Cells,” Immunity 35 (2011): 169-181.

[28] D. Huang, H. Xue, W. Shao, X. Wang, H. Liao, and Y. Ye, “Inhibiting Effect of miR-29 on Proliferation and Migration of Uterine Leiomyoma via the STAT3 Signaling Pathway,” Aging 14 (2022): 1307-1320.

[29] H. H. Uhlig and F. Powrie, “Dendritic Cells and the Intestinal Bacterial Flora: A Role for Localized Mucosal Immune Responses,” Journal of Clinical Investigation 112 (2003): 648-651.

[30] J. R. Schoenborn and C. B. Wilson, “Regulation of Interferon-Gamma During Innate and Adaptive Immune Responses,” Advances in Immunology 96 (2007): 41-101.

[31] R. Ito, M. Shin-Ya, T. Kishida, et al., “Interferon-Gamma is Causatively Involved in Experimental Inflammatory Bowel Disease in Mice,” Clinical and Experimental Immunology 146 (2006): 330-338.

[32] S. Huang, Q. Meng, A. Maminska, and J. D. MacMicking, “Cell-Autonomous Immunity by IFN-Induced GBPs in Animals and Plants,” Current Opinion in Immunology 60 (2019): 71-80.

[33] A. Malik, D. Sharma, R. Aguirre-Gamboa, et al., “Epithelial IFNγ Signalling and Compartmentalized Antigen Presentation Orchestrate Gut Immunity,” Nature 623 (2023): 1044-1052.

[34] A. V. Villarino, Y. Kanno, and J. J. O'Shea, “Mechanisms and Consequences of Jak-STAT Signaling in the Immune System,” Nature Immunology 18 (2017): 374-384.

[35] W. J. Sandborn, C. Su, B. E. Sands, et al., “Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis,” New England Journal of Medicine 376 (2017): 1723-1736.

[36] D. van der Heijde, V. Strand, Y. Tanaka, et al., “Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study,” Arthritis and Rheumatology 71 (2019): 878-891.

[37] S. Zundler and M. F. Neurath, “Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer,” Vaccines (Basel) 4 (2016): 5, https://doi.org/10.3390/vaccines4010005.

[38] L. Xiao, X. X. Ma, J. Luo, et al., “Circular RNA CircHIPK3 Promotes Homeostasis of the Intestinal Epithelium by Reducing MicroRNA 29b Function,” Gastroenterology 161 (2021): 1303-1317.e3.

[39] E. Mizoguchi, D. Low, Y. Ezaki, and T. Okada, “Recent Updates on the Basic Mechanisms and Pathogenesis of Inflammatory Bowel Diseases in Experimental Animal Models,” Intestinal Research 18 (2020): 151-167.

[40] S. Danese, E. Schabel, M. A. Ainsworth, and L. Peyrin-Biroulet, “Challenges and Opportunities for IBD Drug Development: From Early Stage to Regulatory Approval,” Gut 69 (2020): 1157-1161.

[41] F. Rieder, S. Kessler, M. Sans, and C. Fiocchi, “Animal Models of Intestinal Fibrosis: New Tools for the Understanding of Pathogenesis and Therapy of Human Disease,” American Journal of Physiology Gastrointestinal and Liver Physiology 303 (2012): G786-G801, https://doi.org/10.1152/ajpgi.00059.2012.

RIGHTS & PERMISSIONS

2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.