Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II–restricted cytotoxic T lymphocytes
Open accessAbstract
TCRαβ thymocytes differentiate into either CD8αβ(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4(+) T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II-restricted CD4(+) cytotoxic T lymphocytes.
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The cytotoxic subset overexpressed Eomes, Gzmk, and Ctla2a, genes commonly associated with CD8 T cells and previously described in viral infection and cancer as CD4 cytotoxic T cells.
“cells overexpressing genes such as Eomes, Gzmk, and Ctla2a, which are commonly associated with CD8 T cells (denoted cytotoxic) and were previously described in the context of viral infection and cancer as CD4 cytotoxic T cells (32–34).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [33]
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Park, J., Adoro, S., Guinter, T. I., Erman, B., Alag, A., Catálfamo, M., Kimura, M. Y., Cui, Y., Lucas, P. J., Gress, R. E., et al. (2010) · Nature Immunology · doi:10.1038/ni.1840 · Cited by 5,835 · see citing works
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145 · see citing works
Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria
Ivanov, I. I., Atarashi, K., Manel, N., Brodie, E. L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K. C., Santee, C. A., Lynch, S. V., et al. (2009) · Cell · doi:10.1016/j.cell.2009.09.033 · Cited by 4,554 · see citing works
Self-citationReciprocal T <sub>H</sub> 17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid
Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., & Cheroutre, H. (2007) · Science · doi:10.1126/science.1145697 · Cited by 1,982 · see citing works
Self-citationBetts, M. R., Brenchley, J. M., Price, D. A., Rosa, S. C. D., Douek, D. C., Roederer, M., & Koup, R. A. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(03)00265-5 · Cited by 1,587 · see citing works
Taniuchi, I., Osato, M., Egawa, T., Sunshine, M. J., Bae, S., Komori, T., Ito, Y., & Littman, D. R. (2002) · Cell · doi:10.1016/s0092-8674(02)01111-x · Cited by 732 · see citing works
Self-citationThe light and dark sides of intestinal intraepithelial lymphocytes
Cheroutre, H., Lambolez, F., & Mucida, D. (2011) · Nature Reviews Immunology · doi:10.1038/nri3007 · Cited by 693 · cited 1× · see citing works
“…where a rapid elimination of infected cells is important not only to resist the initial invasion of intracellular pathogens, but also to limit or prevent excessive infiltration of systemically activated cytokine secreting cells that could jeopardize the integrity of the mucosal barrier 38 .”
Self-citationViral mechanisms of immune evasion
Alcamı́, A., & Koszinowski, U. H. (2000) · Immunology Today · doi:10.1016/s0167-5699(00)01699-6 · Cited by 548 · see citing works
Characterization of CD4+ CTLs Ex Vivo
Appay, V., Zaunders, J. J., Papagno, L., Sutton, J., Jaramillo, A., Waters, A., Easterbrook, P., Grey, P., Smith, D. E., McMichael, A. J., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.11.5954 · Cited by 545 · see citing works
Mention, J., Ahmed, M. B., Bègue, B., Barbe, U., Verkarre, V., Asnafi, V., Colombel, J., Cugnenc, P., Ruemmele, F. M., McIntyre, E., et al. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)01047-3 · Cited by 460 · see citing works
Ko, H. S., Fu, S. M., WINCHESTER, R. J., Yu, D. T. Y., & Kunkel, H. G. (1979) · The Journal of Experimental Medicine · doi:10.1084/jem.150.2.246 · Cited by 439 · see citing works
The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment
He, X., He, X. C., Davé, V. P., Zhang, Y., Xiang, H., Nicolas, É., Xu, W., Roe, B. A., & Kappes, D. J. (2005) · Nature · doi:10.1038/nature03338 · Cited by 420 · see citing works
Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis
Woolf, E., Xiao, C., Fainaru, O., Lotem, J., Rosen, D., Negreanu, V., Bernstein, Y., Goldenberg, D., Brenner, O. J., Berke, G., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1232420100 · Cited by 407 · see citing works
Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens
DePaolo, R. W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J. A., Wang, W., Marietta, E. V., Kasarda, D. D., Waldmann, T. A., Murray, J. A., et al. (2011) · Nature · doi:10.1038/nature09849 · Cited by 389 · see citing works
Critical Roles for Transcription Factor GATA-3 in Thymocyte Development
Pai, S., Truitt, M., Ting, C.-N., Leiden, J. M., Glimcher, L. H., & Ho, I. (2003) · Immunity · doi:10.1016/s1074-7613(03)00328-5 · Cited by 312 · see citing works
Sun, G., Liu, X., Mercado, P., Jenkinson, S. R., Kypriotou, M., Feigenbaum, L., Galéra, P., & Bosselut, R. (2005) · Nature Immunology · doi:10.1038/ni1183 · Cited by 275 · see citing works
Peripheral CD4+CD8+ T cells are differentiated effector memory cells with antiviral functions
Nascimbeni, M., Shin, E., Chiriboga, L. A., Kleiner, D. E., & Rehermann, B. (2004) · Blood · doi:10.1182/blood-2003-12-4395 · Cited by 263 · see citing works
GATA-3 Expression Is Controlled by TCR Signals and Regulates CD4/CD8 Differentiation
Hernández‐Hoyos, G., Anderson, M. K., Wang, C., Rothenberg, E. V., & Alberola‐Ila, J. (2003) · Immunity · doi:10.1016/s1074-7613(03)00176-6 · Cited by 254 · see citing works
Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T Cell Development
Setoguchi, R., Tachibana, M., Naoe, Y., Muroi, S., Akiyama, K., Tezuka, C., Okuda, T., & Taniuchi, I. (2008) · Science · doi:10.1126/science.1151844 · Cited by 240 · see citing works
Self-citationBoles, K. S., Barchet, W., Diacovo, T., Cella, M., & Colonna, M. (2005) · Blood · doi:10.1182/blood-2005-02-0817 · Cited by 209 · see citing works
Starting at the Beginning: New Perspectives on the Biology of Mucosal T Cells
Cheroutre, H. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104522 · Cited by 196 · see citing works
Self-citationDoubting the TCR Coreceptor Function of CD8αα
Cheroutre, H., & Lambolez, F. (2008) · Immunity · doi:10.1016/j.immuni.2008.01.005 · Cited by 194 · see citing works
Self-citationHershberg, R. M., Cho, D. H., Youakim, A., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci3201 · Cited by 191 · see citing works
Cytotoxic CD4 T Cells in Antiviral Immunity
Marshall, N. B., & Swain, S. L. (2011) · BioMed Research International · doi:10.1155/2011/954602 · Cited by 184 · see citing works
Intraepithelial lymphocytes in celiac disease immunopathology
Abadie, V., Discepolo, V., & Jabri, B. (2012) · Seminars in Immunopathology · doi:10.1007/s00281-012-0316-x · Cited by 183 · see citing works
Guy‐Grand, D., Malassis-Séris, M., Briottet, C., & VASSALLI, P. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.6.1549 · Cited by 178 · see citing works
Interleukin-15: a new cytokine target for the treatment of inflammatory diseases
McInnes, I. B. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.04.003 · Cited by 173 · see citing works
Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy
Brown, D. M. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.02.008 · Cited by 168 · see citing works
Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate
Muroi, S., Naoe, Y., Miyamoto, C., Akiyama, K., Ikawa, T., Masuda, K., Kawamoto, H., & Taniuchi, I. (2008) · Nature Immunology · doi:10.1038/ni.1650 · Cited by 155 · see citing works
Self-citationIdentification of Pre- and Postselection TCRαβ+ Intraepithelial Lymphocyte Precursors in the Thymus
Gangadharan, D., Lambolez, F., Attinger, A., Wang-Zhu, Y., Sullivan, B. A., & Cheroutre, H. (2006) · Immunity · doi:10.1016/j.immuni.2006.08.018 · Cited by 153 · see citing works
Self-citationBoles, K. S., Stepp, S. E., Bennett, M., et al. (2001) · Immunological Reviews · doi:10.1034/j.1600-065x.2001.1810120.x · Cited by 152 · see citing works
Wang, L., Wildt, K. F., Castro, E., Xiong, Y., Feigenbaum, L., Tessarollo, L., & Bosselut, R. (2008) · Immunity · doi:10.1016/j.immuni.2008.09.019 · Cited by 143 · see citing works
The physiological role of cytotoxic CD4+ T-cells: the holy grail?
Appay, V. (2004) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2004.02605.x · Cited by 126 · see citing works
LeBlanc, P. M., Yeretssian, G., Rutherford, N., Doiron, K., Nadiri, A., Zhu, L., Green, D. R., Gruenheid, S., & Saleh, M. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.02.004 · Cited by 120 · see citing works
Sydora, B. C., Mixter, P. F., Holcombe, H. R., et al. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.6.2179 · Cited by 116 · see citing works
Ellmeier, W., Sunshine, M. J., Losos, K., Hatam, F., & Littman, D. R. (1997) · Immunity · doi:10.1016/s1074-7613(00)80375-1 · Cited by 115 · see citing works
Self-citationRegulation of Th2 Cell Differentiation by mel-18, a Mammalian Polycomb Group Gene
Kimura, M. Y., Koseki, Y., Yamashita, M., Watanabe, N., Shimizu, C., Katsumoto, T., Kitamura, T., Taniguchi, M., Koseki, H., & Nakayama, T. (2001) · Immunity · doi:10.1016/s1074-7613(01)00182-0 · Cited by 114 · see citing works
Self-citationInterleukin 15 is a potent stimulant of intraepithelial lymphocytes
Ebert, E. C. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70022-8 · Cited by 103 · see citing works
Sakaguchi, S., Hombauer, M., Bilić, I., et al. (2010) · Nature Immunology · doi:10.1038/ni.1860 · Cited by 97 · see citing works
Self-citationKhanna, R., Burrows, S. R., Thomson, S. A., et al. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.8.3619 · Cited by 94 · see citing works
Kennedy, J., Vicari, A. P., Saylor, V., Zurawski, S., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., & Zlotnik, A. (2000) · Journal of Leukocyte Biology · doi:10.1002/jlb.67.5.725 · Cited by 89 · see citing works
The Role of ThPOK in Control of CD4/CD8 Lineage Commitment
He, X. C., Park, K., & Kappes, D. J. (2010) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141715 · Cited by 82 · see citing works
Ye, W., Young, J. D., & Liu, C.-C. (1996) · Cellular Immunology · doi:10.1006/cimm.1996.0293 · Cited by 77 · see citing works
Hirose, K., Suzuki, H., Nishimura, H., et al. (1998) · Infection and Immunity · doi:10.1128/iai.66.12.5677-5683.1998 · Cited by 68 · see citing works
TOX Is Required for Development of the CD4 T Cell Lineage Gene Program
Aliahmad, P., Kadavallore, A., de la Torre, B., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101474 · Cited by 67 · see citing works
A Novel Flow Cytometric Assay for Evaluating Cell-Mediated Cytotoxicity
Burkett, M. W., Shafer-Weaver, K., Strobl, S. L., Baseler, M., & Malyguine, A. M. (2005) · Journal of Immunotherapy · doi:10.1097/01.cji.0000165357.11548.6d · Cited by 51 · see citing works
Sasahara, T., Tamauchi, H., Ikewaki, N., & Kubota, K. (1994) · Microbiology and Immunology · doi:10.1111/j.1348-0421.1994.tb01764.x · Cited by 21 · see citing works
Functionally Diverse Subsets in CD4 T Cell Responses Against Influenza
Strutt, T. M., McKinstry, K. K., & Swain, S. L. (2008) · Journal of Clinical Immunology · doi:10.1007/s10875-008-9266-4 · Cited by 19 · see citing works
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- Authors
- Mucida, D., Husain, M. M., Muroi, S., van Wijk, F., Shinnakasu, R., Naoe, Y., Reis, B. S., Huang, Y., Lambolez, F., Docherty, M., Attinger, A., Shui, J.-W., Kim, G., Lena, C. J., Sakaguchi, S., Miyamoto, C., Wang, P., Atarashi, K., Park, Y., Nakayama, T., Honda, K., Ellmeier, W., Kronenberg, M., Taniuchi, I., & Cheroutre, H.
- Affiliations
- La Jolla Institute for Immunology (US)
- RIKEN (JP)
- Rockefeller University (US)
- Medical University of Vienna (AT)
- The University of Tokyo (JP)
- Chiba University (JP)
- Corresponding author
- Taniuchi, Ichiro
- Cheroutre, Hilde
- ORCID
- Venue
- Nature Immunology
- Published
- 2013-01-20
- Volume
- 14
- Issue
- 3
- Pages
- 281-289
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3581083
- OpenAlex
- W2046612588
- Cited by
- 376
- References
- 48
- Citations by year
- 2026: 27 · 2025: 26 · 2024: 27 · 2023: 29 · 2022: 43 · 2021: 25 · 2020: 27 · 2019: 15 · 2018: 27 · 2017: 26 · 2016: 35 · 2015: 19 · 2014: 31 · 2013: 19
- FWCI
- 19.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Crohn's and Colitis Foundation
- CYTED Ciencia y Tecnología para el Desarrollo
- National Institutes of Health (DP1OD006433, 5r01ai050265-13)
- National Institute of General Medical Sciences (DP1GM105384)
- National Institute of Allergy and Infectious Diseases (R01-AI050265)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK046763, F32DK082249, P01 DK46763, R01DK093674)
- National Center for Research Resources (S10RR027366)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- ThPOK, CD4+ T cells, CD8+ cytotoxic T lymphocytes, transcriptional reprogramming, MHC class II restriction, T helper cell differentiation, gut-associated lymphoid tissue, effector T cell differentiation
- MeSH terms
- Animals, Histocompatibility Antigens Class II, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Transcription Factors, Interleukin-7, Mice, Knockout, Homeodomain Proteins, Cell Lineage, Citrobacter rodentium, Mice, Thymocytes
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