MALT1 protease function in regulatory T cells induces MYC activity to promote mitochondrial function and cellular expansion.
Immune regulation
Regulatory T cells
Signal transduction
TCR
Journal
European journal of immunology
ISSN: 1521-4141
Titre abrégé: Eur J Immunol
Pays: Germany
ID NLM: 1273201
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
06
09
2021
received:
11
05
2021
pubmed:
21
10
2021
medline:
10
2
2022
entrez:
20
10
2021
Statut:
ppublish
Résumé
Regulatory T cells (Tregs) are essential for the inhibition of immunity and the maintenance of tissue homeostasis. Signals from the T-cell antigen receptor (TCR) are critical for early Treg development, their expansion, and inhibitory activity. Although TCR-engaged activation of the paracaspase MALT1 is important for these Treg activities, the MALT1 effector pathways in Tregs remain ill-defined. Here, we demonstrate that MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs. These mechanisms are important for Treg-intrinsic mitochondrial function, optimal respiratory capacity, and homeostatic Treg proliferation. Consistently, conditional deletion of Myc in Tregs results similar to MALT1 inactivation in a lethal autoimmune inflammatory syndrome. Together, these results identify a MALT1 protease-mediated link between TCR signaling in Tregs and MYC control that coordinates metabolism and Treg expansion for the maintenance of immune homeostasis.
Identifiants
pubmed: 34668583
doi: 10.1002/eji.202149355
doi:
Substances chimiques
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Malt1 protein, mouse
EC 3.4.22.-
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
85-95Informations de copyright
© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.
Références
Nishikawa, H. and Sakaguchi, S., Regulatory T cells in tumor immunity. Int. J. Cancer. 2010. 127: 759-767.
Tanaka, A. and Sakaguchi, S., Targeting Treg cells in cancer immunotherapy. Eur. J. Immunol. 2019. 49: 1140-1146.
Vahl, J. C., Drees, C., Heger, K., Heink, S., Fischer, J. C., Nedjic, J., Ohkura, N. et al., Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 2014. 41: 722-736.
Levine, A. G., Arvey, A., Jin, W. and Rudensky, A. Y., Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 2014. 15: 1070-1078.
Rosenbaum, M., Gewies, A., Pechloff, K., Heuser, C., Engleitner, T., Gehring, T., Hartjes, L., et al ., Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. Nat. Commun. 2019. 10: 2352.
Di Pilato, M., Kim, E. Y., Cadilha, B. L., Prussmann, J. N., Nasrallah, M. N., Seruggia, D., Usmani, S. M. et al., Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019. 570: 112-116.
Cheng, L., Deng, N., Yang, N., Zhao, X. and Lin, X., Malt1 protease is critical in maintaining function of regulatory T cells and may be a therapeutic target for antitumor immunity. J. Immunol. 2019. 202: 3008-3019.
Yang, D., Zhao, X. and Lin, X., Bcl10 is required for the development and suppressive function of Foxp3(+) regulatory T cells. Cell Mol Immunol. 2021. 18: 206-218.
Turvey, S. E., Durandy, A., Fischer, A., Fung, S. Y., Geha, R. S., Gewies, A., Giese, T. et al., The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency. J. Allergy Clin. Immunol. 2014. 134: 276-284.
Sun, L., Deng, L., Ea, C. K., Xia, Z. P. and Chen, Z. J., The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell. 2004. 14: 289-301.
Ruland, J. and Hartjes, L., CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat. Rev. Immunol. 2019. 19: 118-134.
Monopteros Therapeutics, I. A study of MPT-0118 in subjects with advanced or metastatic refractory solid tumors. 2023.
Janssen, R. and Development, L. L. C., A study of JNJ-67856633 in participants With non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 2022.
Jaworski, M. and Thome, M., The paracaspase MALT1: biological function and potential for therapeutic inhibition. Cell. Mol. Life Sci. 2016. 73: 459-473.
Gewies, A., Gorka, O., Bergmann, H., Pechloff, K., Petermann, F., Jeltsch, K. M., Rudelius, M. et al., Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell Rep. 2014. 9: 1292-1305.
Bornancin, F., Renner, F., Touil, R., Sic, H., Kolb, Y., Touil-Allaoui, I., Rush, J. S. et al., Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. J. Immunol. 2015. 194: 3723-3734.
Jaworski, M., Marsland, B. J., Gehrig, J., Held, W., Favre, S., Luther, S. A., Perroud, M. et al., Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. EMBO J. 2014. 33: 2765-2781.
Yu, J. W., Hoffman, S., Beal, A. M., Dykon, A., Ringenberg, M. A., Hughes, A. C., Dare, L. et al., MALT1 protease activity is required for innate and adaptive immune responses. PLoS One 2015. 10: e0127083.
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T. et al., CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008. 322: 271-275.
Srinivas, S., Watanabe, T., Lin, C. S., William, C. M., Tanabe, Y., Jessell, T. M. and Costantini, F., Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 2001. 1: 4.
Nagel, D., Spranger, S., Vincendeau, M., Grau, M., Raffegerst, S., Kloo, B., Hlahla, D. et al., Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell. 2012. 22: 825-837.
Johnson, D. G., Schwarz, J. K., Cress, W. D. and Nevins, J. R., Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 1993. 365: 349-352.
Grumont, R., Lock, P., Mollinari, M., Shannon, F. M., Moore, A. and Gerondakis, S., The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-Myc expression. Immunity 2004. 21: 19-30.
Grinberg-Bleyer, Y., Oh, H., Desrichard, A., Bhatt, D. M., Caron, R., Chan, T. A., Schmid, R. M. et al., NF-kappaB c-Rel is crucial for the regulatory T cell immune checkpoint in cancer. Cell 2017. 170: 1096-1108 e1013.
Shono, Y., Tuckett, A. Z., Ouk, S., Liou, H. C., Altan-Bonnet, G., Tsai, J. J., Oyler, J. E. et al., A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discov. 2014. 4: 578-591.
Wang, W., Tam, W. F., Hughes, C. C., Rath, S. and Sen, R., c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity 1997. 6: 165-174.
de Alboran, I. M., O'Hagan, R. C., Gartner, F., Malynn, B., Davidson, L., Rickert, R., Rajewsky, K. et al., Analysis of c-Myc function in normal cells via conditional gene-targeted mutation. Immunity 2001. 14: 45-55.
Saravia, J., Zeng, H., Dhungana, Y., Bastardo Blanco, D., Nguyen, T. M., Chapman, N. M., Wang, Y. et al., Homeostasis and transitional activation of regulatory T cells require c-Myc. Sci. Adv. 2020. 6, eaaw6443.
Tommasini, A., Ferrari, S., Moratto, D., Badolato, R., Boniotto, M., Pirulli, D., Notarangelo, L. D. et al., X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin. Exp. Immunol. 2002. 130: 127-130.
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L. et al., The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011. 35: 871-882.
Pourdehnad, M., Truitt, M. L., Siddiqi, I. N., Ducker, G. S., Shokat, K. M. and Ruggero, D., Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl. Acad. Sci. U. S. A. 2013. 110: 11988-11993.
Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. and Dang, C. V., MYC, metabolism, and cancer. Cancer Discov. 2015. 5: 1024-1039.
Gerriets, V. A., Kishton, R. J., Nichols, A. G., Macintyre, A. N., Inoue, M., Ilkayeva, O., Winter, P. S. et al., Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 2015. 125: 194-207.
Chapman, N. M., Zeng, H., Nguyen, T. M., Wang, Y., Vogel, P., Dhungana, Y., Liu, X. et al., mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat. Commun. 2018. 9: 2095.
Angelin, A., Gil-de-Gomez, L., Dahiya, S., Jiao, J., Guo, L., Levine, M. H., Wang, Z. et al., Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017. 25: 1282-1293 e1287.
Goetzman, E. S. and Prochownik, E. V., The role for Myc in coordinating glycolysis, oxidative phosphorylation, glutaminolysis, and fatty acid metabolism in normal and neoplastic tissues. Front Endocrinol (Lausanne). 2018. 9: 129.
Huang, M. J., Cheng, Y. C., Liu, C. R., Lin, S. and Liu, H. E., A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp. Hematol. 2006. 34: 1480-1489.
Graves, J. A., Wang, Y., Sims-Lucas, S., Cherok, E., Rothermund, K., Branca, M. F., Elster, J. et al., Mitochondrial structure, function and dynamics are temporally controlled by c-Myc. PLoS One 2012. 7: e37699.
Edmunds, L. R., Sharma, L., Wang, H., Kang, A., d'Souza, S., Lu, J., McLaughlin, M. et al., c-Myc and AMPK control cellular energy levels by cooperatively regulating mitochondrial structure and function. PLoS One 2015. 10: e0134049.
Morrish, F. and Hockenbery, D., MYC and mitochondrial biogenesis. Cold Spring Harb. Perspect. Med. 2014. 4: a014225.
Dai, B., Grau, M., Juilland, M., Klener, P., Horing, E., Molinsky, J., Schimmack, G. et al., B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Blood. 2017. 129: 333-346.
Rubtsov, Y. P., Niec, R. E., Josefowicz, S., Li, L., Darce, J., Mathis, D., Benoist, C. et al., Stability of the regulatory T cell lineage in vivo. Science. 2010. 329: 1667-1671.
Parekh, S., Ziegenhain, C., Vieth, B., Enard, W. and Hellmann, I., The impact of amplification on differential expression analyses by RNA-seq. Sci. Rep. 2016. 6: 25533.
Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I. et al., Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 2015. 161: 1202-1214.
Core Team R, R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 2014.
Love, M. I., Huber, W. and Anders, S., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014. 15: 550.
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W. and Smyth, G. K., limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic. Acids. Res. 2015. 43: e47.
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A. et al., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U. S. A. 2005. 102: 15545-15550.
Cossarizza, A., Chang, H. D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W. et al., Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur. J. Immunol. 2019. 49: 1457-1973.