Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (4) : 451-462
Deubiquitinases as pivotal regulators of T cell functions
Xiao-Dong Yang1, Shao-Cong Sun2,3()
1. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA
3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
 Download: PDF(300 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

Keywords deubiquitinase      ubiquitination      T cell activation      T cell differentiation      T cell tolerance     
Corresponding Authors: Shao-Cong Sun   
Just Accepted Date: 02 July 2018   Online First Date: 30 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Xiao-Dong Yang,Shao-Cong Sun. Deubiquitinases as pivotal regulators of T cell functions[J]. Front. Med., 2018, 12(4): 451-462.
Fig.1  Ubiquitination is a reversible reaction counter regulated by ubiquitinating enzymes and DUBs. (A) Ubiquitin conjugation onto a target protein is catalyzed by the sequential action of three ubiquitinating enzymes, E1, E2, and E3. Mammalian cells have 2 E1s, about 40 E2s, and more than 600 E3s. E3s mediate substrate recognition and determine the specificity of protein ubiquitination. Ubiquitination can occur via formation of different types of ubiquitin chains and regulate diverse cellular functions. Deubiquitinases (DUBs) cleave ubiquitin chains and deconjugate ubiquitin from substrates, thereby reversing the ubiquitination reaction. (B) DUBs are classified into six families, including five families of cysteine proteases and one family of metalloprotease.
Fig.2  DUBs regulating TCR signaling. DUBs regulate both TCR-proximal and downstream signaling events. Otud7b deconjugates non-degradative ubiquitin chains from Zap70 to prevent its association with a negative-regulatory phosphatase, Sts1 or Sts2, thereby promoting Zap70 activation. USP9X deubiquitinates Zap70 to prevent endosome sequestration of ubiquitinated Zap70. USP15 deubiquitinates and stabilizes MDM2, an E3 ligase mediating ubiquitination and proteolysis of an NFAT family member, NFATc2, and negatively regulating TCR signaling. Several DUBs, including A20, CYLD, and USP18, deconjugate K63-linked ubiquitin chains from the TAK1/IKK signaling complex to negatively regulate this signaling pathway.
Fig.3  DUBs involved in regulation of CD4+ T cell differentiation. DUBs may regulate CD4+ T cell differentiation through controlling cytokine production during the early phase of T cell activation or regulating the lineage transcription factors during the subsequent phase of differentiation. In addition to the polarizing cytokine IL-12, IFNg produced during T cell activation promotes Th1 differentiation. USP15 and USP18 attenuate Th1 differentiation by negatively regulating IFNg induction, whereas Otud7b has the opposite function. USP18 promotes Th17 cell differentiation by inhibiting production of the Th17-inhibitory cytokine IL-2. Several DUBs (USP4, USP15, and USP17) promote Th17 polarization by stabilizing or facilitating the function of RORgt, whereas DUBA inhibits Th17 polarization by promoting RORgt degradation. The DUB Trabid promotes Th1 and Th17 cell differentiation and inflammation by facilitating TLR-induced expression of the polarizing cytokines IL-12 and IL-23.
DUB Family Function Target References
CYLD USP Thymocyte development LCK, IKK [25, 27]
Survival of immature NKT cells IKK [29]
T cell activation TAK1, IKK [39, 40]
Treg development IKK, Smad7 [73, 75, 76]
USP4 USP Th17 differentiation RORgt [64]
USP7 USP Treg function Foxp3, Tip60 [7981]
USP8 USP Thymocyte maturation CHMP5 [35, 36]
USP9X USP TCR signaling Bcl10 [48]
TCR signaling and central tolerance Zap70 [53, 54]
TCR signaling Themis [55]
USP10 USP Unknown T-bet [60]
USP15 USP T cell activation and differentiation MDM2 [49]
Th17 differentiation RORgt [65]
USP17 USP Th17 differentiation RORgt [63]
USP18 USP Th17 differentiation TAK1-TAB1 [41]
A20 OTU NKT cell differentiation MALT1 [33]
CD8 T cell activation NF-kB pathway [43, 44]
CD4 T cell survival RIPK3 [45]
T cell survival mTORC1 [46]
Cell-extrinsic regulation of Th1 and Th17 cell differentiation NF-kB pathway [6870]
Treg development NF-kB pathway [77]
Otud7b OTU T cell activation and differentiation Zap70 [50]
DUBA OTU Th17 differentiation UBR5 [61]
Zranb1 OTU Cell-extrinsic regulation of Th1 and Th17 cell differentiation Jmjd2b [67]
Tab.1  Deubiquitinases involved in T cell regulation
1 Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009; 27(1): 591–619 pmid: 19132916
2 Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010; 28(1): 445–489 pmid: 20192806
3 Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 2005; 435(7042): 590–597 pmid: 15931211
4 Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol 2012; 4(6): a006957 pmid: 22661634
5 O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327(5969): 1098–1102 pmid: 20185720
6 Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014; 41(4): 529–542 pmid: 25367570
7 Damsker JM, Hansen AM, Caspi RR. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 2010; 1183(1): 211–221 pmid: 20146717
8 Zhang N, Bevan MJ. CD8+ T cells: foot soldiers of the immune system. Immunity 2011; 35(2): 161–168 pmid: 21867926
9 Halle S, Halle O, Förster R. Mechanisms and dynamics of T cell-mediated cytotoxicity in vivo. Trends Immunol 2017; 38(6): 432–443 pmid: 28499492
10 Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9(1): 271–296 pmid: 1910679
11 Kennedy R, Celis E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 2008; 222(1): 129–144 pmid: 18363998
12 Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev 2009; 228(1): 9–22 pmid: 19290918
13 Ohashi PS. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2002; 2(6): 427–438 pmid: 12093009
14 Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67(1): 425–479 pmid: 9759494
15 Kulathu Y, Komander D. Atypical ubiquitylation — the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 2012; 13(8): 508–523 pmid: 22820888
16 Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. J Cell Sci 2016; 129(5): 875–880 pmid: 26906419
17 Ikeda F. Linear ubiquitination signals in adaptive immune responses. Immunol Rev 2015; 266(1): 222–236 pmid: 26085218
18 Chen J, Chen ZJ. Regulation of NF-kB by ubiquitination. Curr Opin Immunol 2013; 25(1): 4–12 pmid: 23312890
19 Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell 2005; 123(5): 773–786 pmid: 16325574
20 Abdul Rehman SA, Kristariyanto YA, Choi SY, Nkosi PJ, Weidlich S, Labib K, Hofmann K, Kulathu Y. MINDY-1 is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol Cell 2016; 63(1): 146–155 pmid: 27292798
21 Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 2017; 86(1): 159–192 pmid: 28498721
22 Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2(5): 309–322 pmid: 12033737
23 Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol 2014; 14(6): 377–391 pmid: 24830344
24 Hu H, Sun SC. Ubiquitin signaling in immune responses. Cell Res 2016; 26(4): 457–483 pmid: 27012466
25 Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 2006; 7(4): 411–417 pmid: 16501569
26 Sun SC. CYLD: a tumor suppressor deubiquitinase regulating NF-kB activation. Cell Death Differ 2010; 17(1): 25–34 doi:10.1038/cdd.2009.43
pmid: 19373246
27 Tsagaratou A, Trompouki E, Grammenoudi S, Kontoyiannis DL, Mosialos G. Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs positive selection in a NF-kB essential modulator-dependent manner. J Immunol 2010; 185(4): 2032–2043 pmid: 20644164
28 Reissig S, Hövelmeyer N, Tang Y, Weih D, Nikolaev A, Riemann M, Weih F, Waisman A. The deubiquitinating enzyme CYLD regulates the differentiation and maturation of thymic medullary epithelial cells. Immunol Cell Biol 2015; 93(6): 558–566 pmid: 25601276
29 Lee AJ, Zhou X, Chang M, Hunzeker J, Bonneau RH, Zhou D, Sun SC. Regulation of natural killer T-cell development by deubiquitinase CYLD. EMBO J 2010; 29(9): 1600–1612 pmid: 20224552
30 Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336 pmid: 17150027
31 Crosby CM, Kronenberg M. Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 2016; 68(8): 639–648 pmid: 27368411
32 Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S, Harada M, Endo TA, Watanabe T, Ohara O, Taniguchi M. Alternative pathway for the development of Va14+ NKT cells directly from CD4−CD8− thymocytes that bypasses the CD4+CD8+ stage. Nat Immunol 2017; 18(3): 274–282 pmid: 28135253
33 Drennan MB, Govindarajan S, Verheugen E, Coquet JM, Staal J, McGuire C, Taghon T, Leclercq G, Beyaert R, van Loo G, Lambrecht BN, Elewaut D. NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20. J Exp Med 2016; 213(10): 1973–1981 pmid: 27551157
34 Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 2013; 14(11): 1146–1154 pmid: 24097110
35 Dufner A, Kisser A, Niendorf S, Basters A, Reissig S, Schönle A, Aichem A, Kurz T, Schlosser A, Yablonski D, Groettrup M, Buch T, Waisman A, Schamel WW, Prinz M, Knobeloch KP. The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells. Nat Immunol 2015; 16(9): 950–960 pmid: 26214742
36 Adoro S, Park KH, Bettigole SE, Lis R, Shin HR, Seo H, Kim JH, Knobeloch KP, Shim JH, Glimcher LH. Post-translational control of T cell development by the ESCRT protein CHMP5. Nat Immunol 2017; 18(7): 780–790 pmid: 28553951
37 Chen ZJ. Ubiquitination in signaling to and activation of IKK. Immunol Rev 2012; 246(1): 95–106 pmid: 22435549
38 Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep 2006; 7(8): 838–844
pmid: 16845370
39 Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 2007; 204(6): 1475–1485 pmid: 17548520
40 Schmid U, Stenzel W, Koschel J, Raptaki M, Wang X, Naumann M, Matuschewski K, Schlüter D, Nishanth G. The deubiquitinating enzyme cylindromatosis dampens CD8+ T cell responses and is a critical factor for experimental cerebral malaria and blood-brain barrier damage. Front Immunol 2017; 8: 27 pmid: 28203236
41 Liu X, Li H, Zhong B, Blonska M, Gorjestani S, Yan M, Tian Q, Zhang DE, Lin X, Dong C. USP18 inhibits NF-kB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J Exp Med 2013; 210(8): 1575–1590 pmid: 23825189
42 Harhaj EW, Dixit VM. Deubiquitinases in the regulation of NF-kB signaling. Cell Res 2011; 21(1): 22–39 pmid: 21119682
43 Giordano M, Roncagalli R, Bourdely P, Chasson L, Buferne M, Yamasaki S, Beyaert R, van Loo G, Auphan-Anezin N, Schmitt-Verhulst AM, Verdeil G. The tumor necrosis factor α-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. Proc Natl Acad Sci USA 2014; 111(30): 11115–11120 pmid: 25024217
44 Just S, Nishanth G, Buchbinder JH, Wang X, Naumann M, Lavrik I, Schlüter D. A20 curtails primary but augments secondary CD8+ T cell responses in intracellular bacterial infection. Sci Rep 2016; 6(1): 39796 pmid: 28004776
45 Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, Ma A. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 2015; 16(6): 618–627 pmid: 25939025
46 Matsuzawa Y, Oshima S, Takahara M, Maeyashiki C, Nemoto Y, Kobayashi M, Nibe Y, Nozaki K, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Ma A, Watanabe M. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy 2015; 11(7): 1052–1062 pmid: 26043155
47 Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 2013; 51(3): 283–296 pmid: 23911927
48 Park Y, Jin HS, Liu YC. Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex. Proc Natl Acad Sci USA 2013; 110(23): 9433–9438 pmid: 23690623
49 Zou Q, Jin J, Hu H, Li HS, Romano S, Xiao Y, Nakaya M, Zhou X, Cheng X, Yang P, Lozano G, Zhu C, Watowich SS, Ullrich SE, Sun SC. USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 2014; 15(6): 562–570 pmid: 24777531
50 Hu H, Wang H, Xiao Y, Jin J, Chang JH, Zou Q, Xie X, Cheng X, Sun SC. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J Exp Med 2016; 213(3): 399–414 pmid: 26903241
51 Carpino N, Chen Y, Nassar N, Oh HW. The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways. Mol Immunol 2009; 46(16): 3224–3231 pmid: 19733910
52 Yang M, Chen T, Li X, Yu Z, Tang S, Wang C, Gu Y, Liu Y, Xu S, Li W, Zhang X, Wang J, Cao X. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation. Nat Immunol 2015; 16(12): 1253–1262 pmid: 26390156
53 Naik E, Webster JD, DeVoss J, Liu J, Suriben R, Dixit VM. Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X. J Exp Med 2014; 211(10): 1947–1955 pmid: 25200027
54 Naik E, Dixit VM. Usp9X is required for lymphocyte activation and homeostasis through its control of ZAP70 ubiquitination and PKCb kinase activity. J Immunol 2016; 196(8): 3438–3451 pmid: 26936881
55 Garreau A, Blaize G, Argenty J, Rouquié N, Tourdès A, Wood SA, Saoudi A, Lesourne R. Grb2-mediated recruitment of USP9X to LAT enhances themis stability following thymic selection. J Immunol 2017; 199(8): 2758–2766 pmid: 28877990
56 Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD4+ T cells toward distinct T-helper cell subsets. Immunol Rev 2013; 252(1): 12–23 PMID:23405892
57 Tu E, Chia CPZ, Chen W, Zhang D, Park SA, Jin W, Wang D, Alegre ML, Zhang YE, Sun L, Chen W. T Cell receptor-regulated TGF-β type I receptor expression determines T cell quiescence and activation. Immunity2018; 48(4): 745–759e6
58 Walsh KP, Mills KH. Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol 2013; 34(11): 521–530 pmid: 23973621
59 Berenson LS, Ota N, Murphy KM. Issues in T-helper 1 development—resolved and unresolved. Immunol Rev 2004; 202(1): 157–174 pmid: 15546392
60 Pan L, Chen Z, Wang L, Chen C, Li D, Wan H, Li B, Shi G. Deubiquitination and stabilization of T-bet by USP10. Biochem Biophys Res Commun 2014; 449(3): 289–294 pmid: 24845384
61 Rutz S, Kayagaki N, Phung QT, Eidenschenk C, Noubade R, Wang X, Lesch J, Lu R, Newton K, Huang OW, Cochran AG, Vasser M, Fauber BP, DeVoss J, Webster J, Diehl L, Modrusan Z, Kirkpatrick DS, Lill JR, Ouyang W, Dixit VM. Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature 2015; 518(7539): 417–421 pmid: 25470037
62 Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM. DUBA: a deubiquitinase that regulates type I interferon production. Science 2007; 318(5856): 1628–1632 pmid: 17991829
63 Han L, Yang J, Wang X, Wu Q, Yin S, Li Z, Zhang J, Xing Y, Chen Z, Tsun A, Li D, Piccioni M, Zhang Y, Guo Q, Jiang L, Bao L, Lv L, Li B. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor gt (RORgt) in Th17 cells. J Biol Chem 2014; 289(37): 25546–25555 pmid: 25070893
64 Yang J, Xu P, Han L, Guo Z, Wang X, Chen Z, Nie J, Yin S, Piccioni M, Tsun A, Lv L, Ge S, Li B. Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORgt. J Immunol 2015; 194(9): 4094–4097 pmid: 25821221
65 He Z, Wang F, Ma J, Sen S, Zhang J, Gwack Y, Zhou Y, Sun Z. Ubiquitination of RORgt at lysine 446 limits Th17 differentiation by controlling coactivator recruitment. J Immunol 2016; 197(4): 1148–1158 pmid: 27430721
66 Zou Q, Jin J, Xiao Y, Zhou X, Hu H, Cheng X, Kazimi N, Ullrich SE, Sun SC. T cell intrinsic USP15 deficiency promotes excessive IFN-g production and an immunosuppressive tumor microenvironment in MCA-induced fibrosarcoma. Cell Reports 2015; 13(11): 2470–2479 pmid: 26686633
67 Jin J, Xie X, Xiao Y, Hu H, Zou Q, Cheng X, Sun SC. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 2016; 17(3): 259–268 pmid: 26808229
68 Kool M, van Loo G, Waelput W, De Prijck S, Muskens F, Sze M, van Praet J, Branco-Madeira F, Janssens S, Reizis B, Elewaut D, Beyaert R, Hammad H, Lambrecht BN. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 2011; 35(1): 82–96 pmid: 21723156
69 Hammer GE, Turer EE, Taylor KE, Fang CJ, Advincula R, Oshima S, Barrera J, Huang EJ, Hou B, Malynn BA, Reizis B, DeFranco A, Criswell LA, Nakamura MC, Ma A. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 2011; 12(12): 1184–1193 pmid: 22019834
70 Liang J, Huang HI, Benzatti FP, Karlsson AB, Zhang JJ, Youssef N, Ma A, Hale LP, Hammer GE. Inflammatory Th1 and Th17 in the intestine are each driven by functionally specialized dendritic cells with distinct requirements for MyD88. Cell Reports 2016; 17(5): 1330–1343 pmid: 27783947
71 Wang L, Hong B, Jiang X, Jones L, Chen SY, Huang XF. A20 controls macrophage to elicit potent cytotoxic CD4+ T cell response. PLoS One 2012; 7(11): e48930 pmid: 23145026
72 Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133(5): 775–787 pmid: 18510923
73 Lee AJ, Wu X, Cheng H, Zhou X, Cheng X, Sun SC. CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. J Biol Chem 2010; 285(21): 15696–15703 pmid: 20233721
74 Oh H, Ghosh S. NF-kB: roles and regulation in different CD4+ T-cell subsets. Immunol Rev 2013; 252(1): 41–51 pmid: 23405894
75 Zhao Y, Thornton AM, Kinney MC, Ma CA, Spinner JJ, Fuss IJ, Shevach EM, Jain A. The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor b (TGF-b) signaling and the development of regulatory T cells. J Biol Chem 2011; 286(47): 40520–40530 pmid: 21931165
76 Reissig S, Hövelmeyer N, Weigmann B, Nikolaev A, Kalt B, Wunderlich TF, Hahn M, Neurath MF, Waisman A. The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 2012; 189(10): 4770–4776 pmid: 23066153
77 Fischer JC, Otten V, Kober M, Drees C, Rosenbaum M, Schmickl M, Heidegger S, Beyaert R, van Loo G, Li XC, Peschel C, Schmidt-Supprian M, Haas T, Spoerl S, Poeck H. A20 restrains thymic regulatory T cell development. J Immunol 2017; 199(7): 2356–2365 pmid: 28842469
78 Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X, Sun SC. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 2012; 13(5): 481–490 pmid: 22484734
79 van Loosdregt J, Coffer PJ. Post-translational modification networks regulating FOXP3 function. Trends Immunol 2014; 35(8): 368–378 pmid: 25047417
80 van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE, Meerding J, Berkers CR, Barbi J, Gröne A, Sijts AJ, Maurice MM, Kalkhoven E, Prakken BJ, Ovaa H, Pan F, Zaiss DM, Coffer PJ. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 2013; 39(2): 259–271 pmid: 23973222
81 Wang L, Kumar S, Dahiya S, Wang F, Wu J, Newick K, Han R, Samanta A, Beier UH, Akimova T, Bhatti TR, Nicholson B, Kodrasov MP, Agarwal S, Sterner DE, Gu W, Weinstock J, Butt TR, Albelda SM, Hancock WW. Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 2016; 13: 99–112 pmid: 27769803
82 Xiao Y, Nagai Y, Deng G, Ohtani T, Zhu Z, Zhou Z, Zhang H, Ji MQ, Lough JW, Samanta A, Hancock WW, Greene MI. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Reports 2014; 7(5): 1471–1480 pmid: 24835996
83 Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Heride C, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Lancia DR, Caravella JA, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy VV, Talbot AC, Buckmelter AJ, Wang M, McKinnon CL, Saab F, McGouran JF, Century H, Gersch M, Pittman MS, Marshall CG, Raynham TM, Simcox M, Stewart LMD, McLoughlin SB, Escobedo JA, Bair KW, Dinsmore CJ, Hammonds TR, Kim S, Urbé S, Clague MJ, Kessler BM, Komander D. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 2017; 550(7677): 481–486 pmid: 29045389
84 Kategaya L, Di Lello P, Rougé L, Pastor R, Clark KR, Drummond J, Kleinheinz T, Lin E, Upton JP, Prakash S, Heideker J, McCleland M, Ritorto MS, Alessi DR, Trost M, Bainbridge TW, Kwok MCM, Ma TP, Stiffler Z, Brasher B, Tang Y, Jaishankar P, Hearn BR, Renslo AR, Arkin MR, Cohen F, Yu K, Peale F, Gnad F, Chang MT, Klijn C, Blackwood E, Martin SE, Forrest WF, Ernst JA, Ndubaku C, Wang X, Beresini MH, Tsui V, Schwerdtfeger C, Blake RA, Murray J, Maurer T, Wertz IE. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 2017; 550(7677): 534–538 pmid: 29045385
Full text