Aging-related alternative splicing landscapes across human T cells
Show Author's Information
Hide Author's Information
Lipeng Mao1,2,§, Yue Zhu1,2,§, Bei Zhang1,2,§, Guangjie Wu3,§, Qiuyue Feng1,2, Oscar Junhong Luo1,2(
)
Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou 510630, China
Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou 510630, China
Department of Microbiology and Immunology, Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou 510630, China
Mao L, Zhu Y, Zhang B, et al. Aging-related alternative splicing landscapes across human T cells. Aging Research, 2023, 1(1): 9340007. https://doi.org/10.26599/AGR.2023.9340007
As age-related diseases escalate, deciphering molecular mechanism of immune aging is vital. T cells, crucial in adaptive immunity, undergo aging-related transformations in quantity and quality. The interconnection between aging and alternative splicing of gene expression in different T cell subtype is still unclear. Thus, we examined age-related gene alternative splicing in numerous immune cell subgroups, constructing an aging-associated atlas for alternative splicing across human T cell subtypes. Our study identified numerous age-related alternative splicing events in genes linked to T cell activation, differentiation, migration, and apoptosis. Genes like PDCD4 and ARCN1 with age group-specific alternative splicing events and implicated in T cell aging hint at potential therapeutic targets for immune aging. Overall, our findings present a comprehensive alternative splicing atlas for healthy aging-related molecular programs, introducing fresh perspectives for T cell transformation regulation during aging, and inspiring new approaches for novel T cell aging intervention molecules and methods.
Aging-related alternative splicing landscapes across human T cells
Show Author's information
Hide Author's Information
Lipeng Mao1,2,§, Yue Zhu1,2,§, Bei Zhang1,2,§, Guangjie Wu3,§, Qiuyue Feng1,2, Oscar Junhong Luo1,2(
)
Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou 510630, China
Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou 510630, China
Department of Microbiology and Immunology, Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou 510630, China
§ These authors contributed equally to this work.
Abstract
As age-related diseases escalate, deciphering molecular mechanism of immune aging is vital. T cells, crucial in adaptive immunity, undergo aging-related transformations in quantity and quality. The interconnection between aging and alternative splicing of gene expression in different T cell subtype is still unclear. Thus, we examined age-related gene alternative splicing in numerous immune cell subgroups, constructing an aging-associated atlas for alternative splicing across human T cell subtypes. Our study identified numerous age-related alternative splicing events in genes linked to T cell activation, differentiation, migration, and apoptosis. Genes like PDCD4 and ARCN1 with age group-specific alternative splicing events and implicated in T cell aging hint at potential therapeutic targets for immune aging. Overall, our findings present a comprehensive alternative splicing atlas for healthy aging-related molecular programs, introducing fresh perspectives for T cell transformation regulation during aging, and inspiring new approaches for novel T cell aging intervention molecules and methods.
Keywords:alternative splicing, aging, T cells, immune aging
Ponnappan, S., Ponnappan, U. Aging and immune function: Molecular mechanisms to interventions. Antioxidants & Redox Signaling, 2011, 14: 1551–1585. https://doi.org/10.1089/ars.2010.3228
Brummelman, J., Pilipow, K., Lugli, E. The single-cell phenotypic identity of human CD8(+) and CD4(+) T cells. International Review of Cell and Molecular Biology, 2018, 341: 63–124. https://doi.org/10.1016/bs.ircmb.2018.05.007
Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., Accardi, G. Immunosenescence and its hallmarks: How to oppose aging strategically? A review of potential options for therapeutic intervention. Frontiers in Immunology, 2019, 10: 2247. https://doi.org/10.3389/fimmu.2019.02247
Lian, J. Y., Yue, Y., Yu, W. N., Zhang, Y. Immunosenescence: A key player in cancer development. Journal of Hematology & Oncology, 2020, 13: 151. https://doi.org/10.1186/s13045-020-00986-z
Baralle, F. E., Giudice, J. Alternative splicing as a regulator of development and tissue identity. Nature ReviewsMolecular Cell Biology, 2017, 18: 437–451. https://doi.org/10.1038/nrm.2017.27
Chao, Y., Jiang, Y., Zhong, M., Wei, K., Hu, C., Qin, Y., Zuo, Y., Yang, L., Shen, Z., Zou, C. Regulatory roles and mechanisms of alternative RNA splicing in adipogenesis and human metabolic health. Cell & Bioscience, 2021, 11: 66. https://doi.org/10.1186/s13578-021-00581-w
Wang, Y., Liu, J., Huang, B. O., Xu, Y. M., Li, J., Huang, L. F., Lin, J., Zhang, J., Min, Q. H., Yang, W. M. et al. Mechanism of alternative splicing and its regulation. Biomedical Reports, 2015, 3: 152–158. https://doi.org/10.3892/br.2014.407
Yabas, M., Elliott, H., Hoyne, G. F. The role of alternative splicing in the control of immune homeostasis and cellular differentiation. International Journal of Molecular Sciences, 2015, 17: 3. https://doi.org/10.3390/ijms17010003
Giles, J. R., Manne, S., Freilich, E., Oldridge, D. A., Baxter, A. E., George, S., Chen, Z., Huang, H., Chilukuri, L., Carberry, M. et al. Human epigenetic and transcriptional T cell differentiation atlas for identifying functional T cell-specific enhancers. Immunity, 2022, 55: 557–574.e7. https://doi.org/10.1016/j.immuni.2022.02.004
Mahnke, Y. D., Brodie, T. M., Sallusto, F., Roederer, M., Lugli, E. The who’s who of T-cell differentiation: Human memory T-cell subsets. European Journal of Immunology, 2013, 43: 2797–2809. https://doi.org/10.1002/eji.201343751
Henning, A. N., Klebanoff, C. A., Restifo, N. P. Silencing stemness in T cell differentiation. Science, 2018, 359: 163–164. https://doi.org/10.1126/science.aar5541
Shen, S., Park, J. W., Lu, Z. X., Lin, L., Henry, M. D., Wu, Y. N., Zhou, Q., Xing, Y. rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Nucleic Acids Research, 2014, 111: E5593–E5601. https://doi.org/10.1073/pnas.1419161111
Pennock, N. D., White, J. T., Cross, E. W., Cheney, E. E., Tamburini, B. A., Kedl, R. M. T cell responses: Naive to memory and everything in between. Advances in Physiology Education, 2013, 37: 273–283. https://doi.org/10.1152/advan.00066.2013
Caccamo, N., Joosten, S. A., Ottenhoff, T. H. M., Dieli, F. Atypical human effector/memory CD4(+) T cells with a naive-like phenotype. Frontiers in Immunology, 2018, 9: 2832. https://doi.org/10.3389/fimmu.2018.02832
Bacchetta, R., Gregori, S., Roncarolo, M. G. CD4+ regulatory T cells: Mechanisms of induction and effector function. Autoimmunity Reviews, 2005, 4: 491–496. https://doi.org/10.1016/j.autrev.2005.04.005
Rocamora-Reverte, L., Melzer, F. L., Würzner, R., Weinberger, B. The complex role of regulatory T cells in immunity and aging. Frontiers in Immunology, 2021, 11: 616949. https://doi.org/10.3389/fimmu.2020.616949
Izumi, K., Brett, M., Nishi, E., Drunat, S., Tan, E. S., Fujiki, K., Lebon, S., Cham, B., Masuda, K., Arakawa, M. et al. ARCN1 mutations cause a recognizable craniofacial syndrome due to COPI-mediated transport defects. Journal of Inherited Metabolic Disease, 2016, 99: 451–459. https://doi.org/10.1016/j.ajhg.2016.06.011
Gattinoni, L., Speiser, D. E., Lichterfeld, M., Bonini, C. T memory stem cells in health and disease. Nature Medicine, 2017, 23: 18–27. https://doi.org/10.1038/nm.4241
Kohli, K., Pillarisetty, V. G., Kim, T. S. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Therapy, 2022, 29: 10–21. https://doi.org/10.1038/s41417-021-00303-x
Li, M. D., Yao, D. L., Zeng, X. B., Kasakovski, D., Zhang, Y. K., Chen, S. H., Zha, X. F., Li, Y. Q., Xu, L. Age related human T cell subset evolution and senescence. Immunity & Ageing, 2019, 16: 24. https://doi.org/10.1186/s12979-019-0165-8
Weinelt, N., van Wijk, S. J. L. Ubiquitin-dependent and-independent functions of OTULIN in cell fate control and beyond. Cell Death and Differentiation, 2021, 28: 493–504. https://doi.org/10.1038/s41418-020-00675-x
Colpitts, S. L., Dalton N. M., Phillip, S. IL-7 receptor expression provides the potential for long-term survival of both CD62Lhigh central memory T cells and Th1 effector cells during Leishmania major infection. Journal of Immunology, 2009, 182: 5702–5711. https://doi.org/10.4049/jimmunol.0803450
Wang, Q., Yang, H. S. The role of Pdcd4 in tumour suppression and protein translation. Biology of the Cell, 2018, 110: 169–177. https://doi.org/10.1111/boc.201800014
Nolz, J. C., Starbeck-Miller, G. R., Harty, J. T. Naive, effector and memory CD8 T-cell trafficking: Parallels and distinctions. Immunotherapy, 2011, 3: 1223–1233. https://doi.org/10.2217/imt.11.100
Kaech, S. M., Wherry, E. J., Ahmed, R. Effector and memory T-cell differentiation: Implications for vaccine development. Nature ReviewsImmunology, 2002, 2: 251–262. https://doi.org/10.1038/nri778
Jiang, W. Q., He, Y. J., He, W. G., Wu, G. S., Zhou, X. L., Sheng, Q. S., Zhong, W. X., Lu, Y. M., Ding, Y. F., Lu, Q., et al. Exhausted CD8+T cells in the tumor immune microenvironment: new pathways to therapy. Frontiers in Immunology, 2021, 11: 622509. https://doi.org/10.3389/fimmu.2020.622509
Matrone, C., Petrillo, F., Nasso, R., Ferretti, G. Fyn tyrosine kinase as harmonizing factor in neuronal functions and dysfunctions. International Journal of Molecular Sciences, 2020, 21: E4444. https://doi.org/10.3390/ijms21124444
Stanton, T., Boxall, S., Hirai, K., Dawes, R., Tonks, S., Yasui, T., Kanaoka, Y., Yuldasheva, N., Ishiko, O., Bodmer, W. et al. A high-frequency polymorphism in exon 6 of the CD45 tyrosine phosphatase gene (PTPRC) resulting in altered isoform expression. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100: 5997–6002. https://doi.org/10.1073/pnas.0931490100
Jun, D. Y., Kim, H., Jang, W. Y., Lee, J. Y., Fukui, K., Kim, Y. H. Ectopic overexpression of LAPTM5 results in lysosomal targeting and induces Mcl-1 down-regulation, Bak activation, and mitochondria-dependent apoptosis in human HeLa cells. PLoS One, 2017, 12: e0176544.
Zhang, H. M., Weyand, C. M., Goronzy, J. J. Hallmarks of the aging T-cell system. The FEBS Journal, 2021, 288: 7123–7142. https://doi.org/10.1111/febs.15770
Bhadra, M., Howell, P., Dutta, S., Heintz, C., Mair, W. B. Alternative splicing in aging and longevity. Human Genetics, 2020, 139: 357–369. https://doi.org/10.1007/s00439-019-02094-6
Salam, N., Rane, S., Das, R., Faulkner, M., Gund, R., Kandpal, U., Lewis, V., Mattoo, H., Prabhu, S., Ranganathan, V. et al. T cell ageing: Effects of age on development, survival & function. The Indian Journal of Medical Research, 2013, 138: 595–608.
Sun, X. P., Nguyen, T., Achour, A., Ko, A., Cifello, J., Ling, C., Sharma, J., Hiroi, T., Zhang, Y. Q., Chia, C. W., et al. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets. The Journal of Clinical Investigation, 2022, 132: e158122. https://doi.org/10.1172/JCI158122
Jergović, M., Contreras, N. A., Nikolich-Žugich, J. Impact of CMV upon immune aging: Facts and fiction. Medical Microbiology and Immunology, 2019, 208: 263–269. https://doi.org/10.1007/s00430-019-00605-w
Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., Kennedy, R. B. Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses. Experimental Gerontology, 2019, 124: 110632. https://doi.org/10.1016/j.exger.2019.110632
Dawes, R., Petrova, S., Liu, Z., Wraith, D., Beverley, P. C., Tchilian, E. Z. Combinations of CD45 isoforms are crucial for immune function and disease. Journal of Immunology, 2006, 176: 3417–3425. https://doi.org/10.4049/jimmunol.176.6.3417
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, C., Zaleski, C., Jha, S., Batut, P., Chaisson, M., Gingera, T. R. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 2013, 29: 15–21. https://doi.org/10.1093/bioinformatics/bts635
This work was supported by grants from the Natural Science Foundation of China (No. 32050410285 to O.J.L.); the Guangzhou Planned Project of Science and Technology (No. 202002020039 to O.J.L.); the Pearl River Talents Scheme of Guangdong Province (No. 2019QN01Y990 to O.J.L.); and the Initial Startup Fund of Jinan University (O.J.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.
Rights and permissions
The articles published in this open access journal are distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Open Access
Issue
Published:
29 May 2023
)
Download citation
FEEDBACK 
TOP