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Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity

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Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity This information is current as Liqing Cheng, Nan Deng, Naixue Yang, Xueqiang Zhao and of October 1, 2021. Xin Lin J Immunol published online 12 April 2019 http://www.jimmunol.org/content/early/2019/04/11/jimmun ol.1801614 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/04/11/jimmunol.180161 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 12, 2019, doi:10.4049/jimmunol.1801614 The Journal of Immunology Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity Liqing Cheng,*,† Nan Deng,*,† Naixue Yang,‡ Xueqiang Zhao,*,† and Xin Lin*,† The paracaspase Malt1 is a key molecule in mediating Ag receptor–induced NF-kB activation in lymphocytes, but the role of Malt1 in the function of regulatory T (Treg) cells is still unclear. In this article, we reported that specific deletion of Malt1 in Treg cells would lead to Scurfy-like lethal autoimmune disease, which was caused by Treg cell dysfunction but not number loss. Interestingly, Foxp3CreMalt1fl/C472A mice, in which Malt1 protease was specifically inactivated in Treg cells, also displayed spontaneous inflam- matory disorders, with severe hair loss and skin hyperplasia. Consistently, Foxp3CreMalt1fl/C472A mice showed enhanced antitumor response because of their decreased function and infiltration of Treg cells, as well as reduced CD8+ T cell exhaustion. Gene expression profiling analysis revealed dysregulated expression pattern of Treg effector genes upon Malt1 deletion or its protease Downloaded from inactivation. Together, our data unraveled a critical role of Malt1, especially its protease activity, in maintaining homeostasis and function of Treg cells. The Journal of Immunology, 2019, 202: 000–000. egulatory T (Treg) cells, a subpopulation of CD4+ TCR-induced NF-kB activation, such as PKCu, Carma1, Bcl10, T cells, are responsible for maintaining immune toler- Malt1, or TAK1, showed impaired Treg cells development, but the R ance and preventing autoimmune disorders by inhibiting detailed mechanism of this process is not fully elucidated (14–18). http://www.jimmunol.org/ activation of effector T cells and immune response (1, 2). Foxp3, In contrast to conventional T cells (Tconv), which show naive located on the X chromosome, is a Treg-specific transcription phenotype at steady-state, Treg cells display an effector-like factor that can orchestrate the development, maintenance, and phenotype with higher expression level of GITR, CD44, and suppressive function of Treg cells (3, 4). Mice with Foxp3 mutant KLRG1 (19, 20). Previous studies have revealed the requirement can develop spontaneous lethal autoimmunity, similar to what is of continuous TCR signaling for maintaining Treg cells homeo- seen in humans, and are known as Scurfy-mice (5, 6). Foxp3 can stasis, especially for effector phenotype (21, 22). Consistently, the cooperate with other transcription factors, such as NF-AT, NF-kB, transcription factor NF-kB, downstream of TCR signaling, can or IRF4, to regulate transcriptional program of Treg cells (7–9). control lineage-specific transcription landscapes and maintain the by guest on October 1, 2021 Treg cells develop in the thymus and require a relatively higher identity and function of Treg cells (2, 19). However, the role of affinity of TCR engagement with self-peptide MHC class II in the intermediate molecules of TCR signaling pathway in Treg cells is presence of CD28 costimulatory signals and IL-2 (1, 10, 11). TCR poorly understood. engagement can induce the intracellular activation of transcription Malt1 is well known to form complex with Carma1 and Bcl10 to factors including NF-kB. c-Rel, one of its subunits, can bind to mediate Ag receptor–induced lymphocyte activation (23, 24). It CNS2 and CNS3 elements of Foxp3 gene promotor region, which was originally identified as a translocation protein fused with facilitates chromatin remodeling and transcription initiation cIAP2 in mucosa-associated lymphoid tissue B cell lymphomas, (7, 12, 13). Indeed, mice with perturbation of genes that mediate leading to constitutive activation of NF-kB, which is critical for lymphoma cells survival and proliferation (25–28). Given the fact *Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, that Malt1 contains a caspase-like domain, which shares homol- China; †Tsinghua University–Peking University Center for Life Sciences, Beijing, ogy with caspase, it is also named as paracaspase (29). Generation ‡ 100084, China; and Tsinghua University School of Medicine, Beijing 100084, China of Malt1-deficient mice provided initial evidence of the function ORCIDs: 0000-0003-0906-1806 (L.C.); 0000-0002-8187-5583 (X.Z.); 0000-0003- of Malt1 in adaptive immune response (23, 24). Upon TCR en- 0956-3654 (X.L.). gagement, Malt1 and Bcl10 will associate with Carma1, and Received for publication December 11, 2018. Accepted for publication March 14, 2019. Malt1 can function as a scaffolding protein to recruit E3 ligase This work was supported in part by National Nature Science Foundation of China TRAF6 to Carma1-Bcl10-Malt1 complex (30–32). The ubiq- Grants 81630058, 81570211, and 91542107 (to X.L.) and 31670904 (to X.Z.) and a uitination modification of Bcl10 and Malt1 will activate IkB start-up fund from Tsinghua University–Peking University Center for Life Sciences. kinase, which induces IkBa phosphorylation, degradation, and The sequencing result presented in this article has been submitted to the Gene release of canonical NF-kB (33). The released NF-kB can trans- Expression Omnibus under accession number GSE124089. locate into the nucleus to initiate transcription programs (34). Address correspondence and reprint requests to Dr. Xin Lin, School of Medicine, Besides its scaffolding function, Malt1 protease activity can also Tsinghua University, 30 Shuangqing Road, Haidian Qu, Beijing 100084, China. E-mail address: [email protected] be activated upon TCR engagement. It can cleave deubiquitinases The online version of this article contains supplemental material. A20 and CYLD, which remove K63 polyubiquitin chains and are Abbreviations used in this article: BM, bone marrow; cKI, conditional KI; cKO, negative regulators of NF-kB or JNK activation, to amplify signal conditional knockout; iTreg, induced Treg; KI, knock-in; KO, knockout; RNA-seq, (35, 36). RelB, a noncanonical NF-kB member that can inhibit RNA sequencing; Tconv, conventional T cell; Tfh, follicular helper T cell; TIL, canonical NF-kB activation, is also a substrate of Malt1 (37). In tumor infiltrating lymphocyte; Treg, regulatory T; WT, wild type. addition, Malt1 has been reported to cleave mRNA-binding pro- Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 teins Roquin and Regnase1 to regulate mRNA stability (38, 39). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801614 2 Malt1 CONTROLS THE FUNCTION OF Treg CELLS The substrates mentioned above can be recognized as negative FITC anti-Foxp3 (clone FJK-16s), eFluor 450 anti-CD44 (clone IM7), regulators of T cell activation, whereas HOIL-1, a member of allophycocyanin-eFluor 780 anti-CD62L (clone MEL-14), allophycocyanin- LUBAC (linear ubiquitin chain assembly complex), was reported eFluor 780 anti-CD45.2 (clone 104), eFluor 450 anti-PD-1 (clone RMPI-30), eFluor 450 anti-IgD (clone 11-26c), eFluor 660 anti-GL7 (clone GL7) were to be a substrate of Malt1 recently, the cleavage of which would purchased from eBioscience; allophycocyanin anti-IFN-g (clone XMG1.2) dampen TCR signaling and prevented T cells from overt activation was purchased from BioLegend. For CXCR5 staining, cells were incubated (40, 41). The physiological role of Malt1 protease activity has not with biotin-labeled anti-CXCR5 (clone 2G8; BD Biosciences) for 1 h on ice, been defined until the generation of Malt1 protease-dead mutant followed by staining with second Ab PE-CF594 Streptavidin (BD Biosci- ences). Foxp3 was stained according to the manufacturer’s protocol from mice. This strain of mice displayed spontaneous autoimmune and Foxp3 staining kit (eBioscience). For cytokine staining, cells were stimulated multiorgan inflammation with defective differentiation of Treg, with 50 ng/ml PMA (Sigma-Aldrich) and 500 ng/ml ionomycin (Sigma- marginal zone B, and B1 B cells (31, 42–44). Although Malt1 and Aldrich) in the presence of GolgiStop (BD Biosciences) for 5 h at 37˚C its protease activity has been well studied in Tconv, their role in and stained for cell surface markers
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