immunology; lymphocyte; cytotoxic lymphocyte; long non-coding RNA; viral infection
Abstract :
[en] The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.
Zhang, Yanyan ; Institute of Immunology PLA, Third Military Medical University, Chongqing, China ; Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
Li, Baohua; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Bai, Qiang ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) ; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Wang, Pengcheng; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Wei, Gang; Human Phenome Institute, Fudan University, Shanghai, China
Li, Zhirong; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Hu, Li; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Tian, Qin; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Zhou, Jing; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Huang, Qizhao; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Wang, Zhiming; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Yue, Shuai; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Wu, Jialin; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Yang, Liuqing ; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States
Zhou, Xinyuan; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Jiang, Lubin; Institute Pasteur of Shanghai, Chinese Academy of Sciences (CAS), Shanghai, China
Ni, Ting; Human Phenome Institute, Fudan University, Shanghai, China
Ye, Lilin ; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
Wu, Yuzhang; Institute of Immunology PLA, Third Military Medical University, Chongqing, China
NSCF - National Natural Science Foundation of China [CN]
Funding text :
This study was supported by grants from the National Natural Science Foundation of China (No. 31800763 to Y.Z.), Special Grant from Postdoctoral Science Foundation of China (No. 2020T130791 to Y.Z.) and the National Key Research and Development Plan of China (No. 2016YFA0502202 to L.Y). We thank Dr. Ting Ni (Fudan University) for the RNA sequencing. We thank Dr. Rafi Ahmed (Emory University) for P14 transgenic mice and retroviral vectors. And we thank Dr. Liuqing Yang (M.D. Anderson Cancer Centre) for the pGEX-3Z vector.
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8 + T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012). DOI: 10.1038/nri3307
Chang, J. T., Wherry, E. J. & Goldrath, A. W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014). DOI: 10.1038/ni.3031
Kurtulus, S. et al. Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim. J. Immunol. 186, 5729–5737 (2011). DOI: 10.4049/jimmunol.1100102
Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63 (2011). DOI: 10.1038/nature10279
Gullicksrud, J. et al. Differential requirements for Tcf1 long isoforms in CD8+ and CD4+ T cell responses to acute viral infection. J. Immunol. 199, 911–919 (2017). DOI: 10.4049/jimmunol.1700595
Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010). DOI: 10.1016/j.immuni.2010.08.002
Prlic, M. & Bevan, M. J. Cutting edge: β-catenin is dispensable for T cell effector differentiation, memory formation, and recall responses. J. Immunol. 187, 1542–1546 (2011). DOI: 10.4049/jimmunol.1100907
Tiemessen, M. M. et al. T cell factor 1 represses CD8+ effector T cell formation and function. J. Immunol. 193, 5480–5487 (2014). DOI: 10.4049/jimmunol.1303417
Atianand, M. K., Caffrey, D. R. & Fitzgerald, K. A. Immunobiology of long noncoding RNAs. Annu. Rev. Immunol. 35, 177–198 (2017). DOI: 10.1146/annurev-immunol-041015-055459
Heward, J. A. & Lindsay, M. A. Long non-coding RNAs in the regulation of the immune response. Trends Immunol. 35, 408–419 (2014). DOI: 10.1016/j.it.2014.07.005
Hu, G. Q. et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat. Immunol. 14, 1190–U1118 (2013). DOI: 10.1038/ni.2712
Jia, H. et al. Genome-wide computational identification and manual annotation of human long noncoding RNA genes. RNA 16, 1478–1487 (2010). DOI: 10.1261/rna.1951310
B, B. et al. Analysis of CD127 and KLRG1 expression on hepatitis C virus-specific CD8+ T cells reveals the existence of different memory T-cell subsets in the peripheral blood and liver. J. Virol. 81, 945 (2007).
Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017). DOI: 10.1038/nature25144
Akondy, R. S. et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature 552, 362–367 (2017). DOI: 10.1038/nature24633
D’Asaro, M. et al. Increase of CCR7− CD45RA+ CD8 T cells (TEMRA) in chronic graft-versus-host disease. Leukemia 20, 545–547 (2006). DOI: 10.1038/sj.leu.2404079
Chaudhry, M. A. Expression pattern of small nucleolar RNA host genes and long non-coding RNA in X-rays-treated lymphoblastoid cells. Int. J. Mol. Sci. 14, 9099–9110 (2013). DOI: 10.3390/ijms14059099
Anding, A. L. et al. Vps13D encodes a ubiquitin-binding protein that is required for the regulation of mitochondrial size and clearance. Curr. Biol. 28, 287–295.e286 (2018). DOI: 10.1016/j.cub.2017.11.064
Velayosbaeza, A. et al. Analysis of the human VPS13 gene family. Genomics 84, 536–549 (2004). DOI: 10.1016/j.ygeno.2004.04.012
Wang, Z. & Zhang, H. Mitophagy: Vps13D couples mitochondrial fission and autophagic clearance. Curr. Biol. 28, R66–R68 (2018). DOI: 10.1016/j.cub.2017.12.017
Bean, B. D. M. et al. Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites. J. Cell Biol. 217, 3593–3607 (2018). DOI: 10.1083/jcb.201804111
Mccausland, M. M. & Crotty, S. Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo. J. Virolog. Methods 147, 167–176 (2008). DOI: 10.1016/j.jviromet.2007.08.025
Alpdogan, O. & Den Brink, M. R. M. V. IL-7 and IL-15: therapeutic cytokines for immunodeficiency. Trends Immunol. 26, 56–64 (2005). DOI: 10.1016/j.it.2004.11.002
Cieri, N. et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121, 573–584 (2013). DOI: 10.1182/blood-2012-05-431718
Nanjappa, S. G., Walent, J. H., Morre, M. & Suresh, M. Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice. J. Clin. Investig. 118, 1027–1039 (2008).
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000). DOI: 10.1038/80868
Kieper, W. C. et al. Overexpression of interleukin (IL)-7 leads to IL-15–independent generation of memory phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002). DOI: 10.1084/jem.20020067
Rubinstein, M. P. et al. IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 112, 3704–3712 (2008). DOI: 10.1182/blood-2008-06-160945
Schluns, K. S. & Lefrançois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003). DOI: 10.1038/nri1052
Petschner, F. et al. Constitutive expression of Bcl‐xL or Bcl‐2 prevents peptide antigen‐induced T cell deletion but does not influence T cell homeostasis after a viral infection. Eur. J. Immunol. 28, 560–569 (1998). DOI: 10.1002/(SICI)1521-4141(199802)28:02<560::AID-IMMU560>3.0.CO;2-Q
Hand, T. W., Morre, M. & Kaech, S. M. Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc. Natl Acad. Sci. USA 104, 11730–11735 (2007). DOI: 10.1073/pnas.0705007104
Levy, D. E. & Lee, C. What does Stat3 do. J. Clin. Investig. 109, 1143–1148 (2002). DOI: 10.1172/JCI0215650
Schuringa, J. J., Wierenga, A. T. J., Kruijer, W. & Vellenga, E. Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood 95, 3765–3770 (2000). DOI: 10.1182/blood.V95.12.3765
Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009). DOI: 10.1126/science.1175870
Ji, Y. et al. Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells. Nat. Immunol. 12, 1230 (2011). DOI: 10.1038/ni.2153
Nikolaev, Y. & Pervushin, K. Structural basis of RNA binding by leucine zipper GCN4. Protein Sci. 21, 667–676 (2012). DOI: 10.1002/pro.2051
Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007). DOI: 10.1056/NEJMoa073687
Goel, R. R. et al. Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome. J. Allergy Clin. Immunol. 147, 746–749 (2020). DOI: 10.1016/j.jaci.2020.07.024
Cui, W. et al. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011). DOI: 10.1016/j.immuni.2011.09.017
Sutherland, A. P. R. et al. IL-21 promotes CD8+ CTL activity via the transcription factor T-bet. J. Immunol. 190, 3977–3984 (2013). DOI: 10.4049/jimmunol.1201730
Tian, Y. & Zajac, A. J. IL-21 and T cell differentiation: consider the context. Trends Immunol. 37, 557–568 (2016). DOI: 10.1016/j.it.2016.06.001
Yu, Q. et al. IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. J. Exp. Med. 200, 797–803 (2004). DOI: 10.1084/jem.20032183
Kassar, N. E. et al. A dose effect of IL-7 on thymocyte development. Blood 104, 1419–1427 (2004). DOI: 10.1182/blood-2004-01-0201
Xu, L. et al. The transcription factor TCF-1 initiates the differentiation of T FH cells during acute viral infection. Nat. Immunol. 16, 991–999 (2015). DOI: 10.1038/ni.3229
Zhu, Y., Wang, W. & Wang, X. Roles of transcriptional factor 7 in production of inflammatory factors for lung diseases. J. Transl. Med. 13, 273–273 (2015). DOI: 10.1186/s12967-015-0617-7
Gattinoni, L., Ji, Y. & Restifo, N. P. Wnt/β-catenin signaling in T-cell immunity and cancer immunotherapy. Clin. Cancer Res. 16, 4695–4701 (2010). DOI: 10.1158/1078-0432.CCR-10-0356
Hrdlickova, B. et al. Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity. Genome Med. 6, 88 (2014). DOI: 10.1186/s13073-014-0088-0
Fu, Y. et al. Aberrantly expressed long non-coding RNAs in CD8+ T cells response to active tuberculosis. J. Cell. Biochem. 118, 4275–4284 (2017). DOI: 10.1002/jcb.26078
Hudson, W. H. et al. Expression of novel long noncoding RNAs defines virus-specific effector and memory CD8+ T cells. Nat. Commun. 10, 196–196 (2019). DOI: 10.1038/s41467-018-07956-7
Chen, Z. & John Wherry, E. T cell responses in patients with COVID-19. Nat. Rev. Immunol. 20, 529–536 (2020). DOI: 10.1038/s41577-020-0402-6
Gao, L. et al. The dichotomous and incomplete adaptive immunity in COVID-19. Reprint at https://www.medrxiv.org/content/10.1101/2020.09.05.20187435v1 (2020).
