T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Faculty of Science Charles University Prague Prague Czech Republic

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Immunity and Cell Communication Division BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

Zobrazit více v PubMed

Alexander J, Payne JA, Murray R, Frelinger JA, Cresswell P (1989) Differential transport requirements of HLA and H-2 class I glycoproteins. Immunogenetics 29:380–388 10.1007/BF00375866 PubMed DOI

Callahan JA, Hammer GE, Agelides A, Duong BH, Oshima S, North J, Advincula R, Shifrin N, Truong HA, Paw J et al (2013) Cutting edge: ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells. J Immunol 191:535–539 10.4049/jimmunol.1203335 PubMed DOI PMC

Chan S, Belmar N, Ho S, Rogers B, Stickler M, Graham M, Lee E, Tran N, Zhang D, Gupta P et al (2022) An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy. Nat Cancer 3:337–354 10.1038/s43018-022-00334-9 PubMed DOI PMC

Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, Hornick NI, Fitzgerald BL, Damo M, Kasmani MY et al (2021) A reservoir of stem-like CD8(+) T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci Immunol 6:eabg7836 10.1126/sciimmunol.abg7836 PubMed DOI PMC

Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M (2014) Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteom 13:2513–252610.1074/mcp.M113.031591 PubMed DOI PMC

David L, Li Y, Ma J, Garner E, Zhang X, Wu H (2018) Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome. Proc Natl Acad Sci USA 115:1499–1504 10.1073/pnas.1721967115 PubMed DOI PMC

Draberova H, Janusova S, Knizkova D, Semberova T, Pribikova M, Ujevic A, Harant K, Knapkova S, Hrdinka M, Fanfani V et al (2020) Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop. EMBO J 39:e104202 10.15252/embj.2019104202 PubMed DOI PMC

Duhen R, Ballesteros-Merino C, Frye AK, Tran E, Rajamanickam V, Chang SC, Koguchi Y, Bifulco CB, Bernard B, Leidner RS et al (2021) Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells. Nat Commun 12:1047 10.1038/s41467-021-21383-1 PubMed DOI PMC

Geuijen C, Tacken P, Wang LC, Klooster R, Van Loo PF, Zhou J, Mondal A, Liu YB, Kramer A, Condamine T et al (2021) A human CD137xPD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat Commun 12:4445 10.1038/s41467-021-24767-5 PubMed DOI PMC

Glez-Vaz J, Azpilikueta A, Ochoa MC, Olivera I, Gomis G, Cirella A, Luri-Rey C, Alvarez M, Perez-Gracia JL, Ciordia S et al (2023) CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects. Sci Adv 9:eadf6692 10.1126/sciadv.adf6692 PubMed DOI PMC

G’Sell RT, Gaffney PM, Powell DW (2015) A20-Binding inhibitor of NF-kappaB activation 1 is a physiologic inhibitor of NF-kappaB: a molecular switch for inflammation and autoimmunity. Arthritis Rheumatol 67:2292–2302 10.1002/art.39245 PubMed DOI PMC

Gurusamy D, Henning AN, Yamamoto TN, Yu Z, Zacharakis N, Krishna S, Kishton RJ, Vodnala SK, Eidizadeh A, Jia L et al (2020) Multi-phenotype CRISPR-Cas9 screen identifies p38 kinase as a target for adoptive immunotherapies. Cancer Cell 37:818–833.e9 10.1016/j.ccell.2020.05.004 PubMed DOI PMC

Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA et al (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8(+) T cells. J Clin Investig 124:4004–4016 10.1172/JCI75051 PubMed DOI PMC

Horkova V, Drobek A, Paprckova D, Niederlova V, Prasai A, Uleri V, Glatzova D, Kraller M, Cesnekova M, Janusova S et al (2023) Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells. Nat Immunol 24:174–185 10.1038/s41590-022-01366-0 PubMed DOI PMC

Huber M, Heink S, Grothe H, Guralnik A, Reinhard K, Elflein K, Hunig T, Mittrucker HW, Brustle A, Kamradt T et al (2009) A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity. Eur J Immunol 39:1716–1725 10.1002/eji.200939412 PubMed DOI

Iwai K (2021) LUBAC-mediated linear ubiquitination: a crucial regulator of immune signaling. Proc Jpn Acad Ser B Phys Biol Sci 97:120–133 10.2183/pjab.97.007 PubMed DOI PMC

Jang Y, Gerbec ZJ, Won T, Choi B, Podsiad A, B Moore B, Malarkannan S, Laouar Y (2018) Cutting edge: check your mice—a point mutation in the Ncr1 locus identified in CD45.1 congenic mice with consequences in mouse susceptibility to infection. J Immunol 200:1982–1987 10.4049/jimmunol.1701676 PubMed DOI PMC

Jun JE, Kulhanek KR, Chen H, Chakraborty A, Roose JP (2019) Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation. Sci Signal 12:eaao0736 10.1126/scisignal.aao0736 PubMed DOI PMC

Knizkova D, Pribikova M, Draberova H, Semberova T, Trivic T, Synackova A, Ujevic A, Stefanovic J, Drobek A, Huranova M et al (2022) CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology. Nat Immunol 23:1644–1652 10.1038/s41590-022-01325-9 PubMed DOI PMC

Kralova J, Glatzova D, Borna S, Brdicka T (2018) Expression of fluorescent fusion proteins in murine bone marrow-derived dendritic cells and macrophages. J Vis Exp 10.3791/58081 PubMed

Kurts C, Miller JF, Subramaniam RM, Carbone FR, Heath WR (1998) Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 188:409–414 10.1084/jem.188.2.409 PubMed DOI PMC

Labun K, Montague TG, Krause M, Cleuren YNT, Tjeldnes H, Valen E (2019) CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res 47:W171–W174 10.1093/nar/gkz365 PubMed DOI PMC

Lafont E, Draber P, Rieser E, Reichert M, Kupka S, De Miguel D, Draberova H, Von Massenhausen A, Bhamra A, Henderson S et al (2018) TBK1 and IKKepsilon prevent TNF-induced cell death by RIPK1 phosphorylation. Nat Cell Biol 20:1389–1399 10.1038/s41556-018-0229-6 PubMed DOI PMC

Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T (2007) Selective depletion of Foxp3(+) regulatory T cells induces a scurfy-like disease. J Exp Med 204:57–63 10.1084/jem.20061852 PubMed DOI PMC

Lanna A, Henson SM, Escors D, Akbar AN (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15:965–972 10.1038/ni.2981 PubMed DOI PMC

Le Guerroue F, Bunker EN, Rosencrans WM, Nguyen JT, Basar MA, Werner A, Chou TF, Wang C, Youle RJ (2023) TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1. Mol Cell 83:927–941.e8 10.1016/j.molcel.2023.02.023 PubMed DOI PMC

Li M, Liu Y, Xu C, Zhao Q, Liu J, Xing M, Li X, Zhang H, Wu X, Wang L et al (2022) Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development. Cell Death Differ 29:2034–2045 10.1038/s41418-022-00994-1 PubMed DOI PMC

Liu X, Qin H, Wu J, Xu J (2018) Association of TNFAIP3 and TNIP1 polymorphisms with systemic lupus erythematosus risk: a meta-analysis. Gene 668:155–165 10.1016/j.gene.2018.05.062 PubMed DOI

Luckel C, Picard FSR, Huber M (2020) Tc17 biology and function: novel concepts. Eur J Immunol 50:1257–1267 10.1002/eji.202048627 PubMed DOI

Martin A, Seignez C, Racoeur C, Isambert N, Mabrouk N, Scagliarini A, Reveneau S, Arnould L, Bettaieb A, Jeannin JF et al (2018) Tumor-derived granzyme B-expressing neutrophils acquire antitumor potential after lipid A treatment. Oncotarget 9:28364–28378 10.18632/oncotarget.25342 PubMed DOI PMC

Masuda T, Tomita M, Ishihama Y (2008) Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J Proteome Res 7:731–740 10.1021/pr700658q PubMed DOI

Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A (2006) ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 281:18482–18488 10.1074/jbc.M601502200 PubMed DOI

Merritt C, Enslen H, Diehl N, Conze D, Davis RJ, Rincon M (2000) Activation of p38 mitogen-activated protein kinase in vivo selectively induces apoptosis of CD8(+) but not CD4(+) T cells. Mol Cell Biol 20:936–946 10.1128/MCB.20.3.936-946.2000 PubMed DOI PMC

Nanda SK, Petrova T, Marchesi F, Gierlinski M, Razsolkov M, Lee KL, Wright SW, Rao VR, Cohen P, Arthur JSC (2019) Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice. Life Sci Alliance 2:e201900533 10.26508/lsa.201900533 PubMed DOI PMC

Nanda SK, Venigalla RK, Ordureau A, Patterson-Kane JC, Powell DW, Toth R, Arthur JS, Cohen P (2011) Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med 208:1215–1228 10.1084/jem.20102177 PubMed DOI PMC

Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Woo T et al (2009) ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature 457:906–909 10.1038/nature07575 PubMed DOI PMC

Owen DL, Mahmud SA, Sjaastad LE, Williams JB, Spanier JA, Simeonov DR, Ruscher R, Huang W, Proekt I, Miller CN et al (2019) Thymic regulatory T cells arise via two distinct developmental programs. Nat Immunol 20:195–205 10.1038/s41590-018-0289-6 PubMed DOI PMC

Palmer E, Drobek A, Stepanek O (2016) Opposing effects of actin signaling and LFA-1 on establishing the affinity threshold for inducing effector T-cell responses in mice. Eur J Immunol 46:1887–1901 10.1002/eji.201545909 PubMed DOI

Perez-Riverol Y, Bai J, Bandla C, Garcia-Seisdedos D, Hewapathirana S, Kamatchinathan S, Kundu DJ, Prakash A, Frericks-Zipper A, Eisenacher M et al (2022) The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res 50:D543–D552 10.1093/nar/gkab1038 PubMed DOI PMC

Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308 10.1038/nprot.2013.143 PubMed DOI PMC

Rappsilber J, Mann M, Ishihama Y (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2:1896–1906 10.1038/nprot.2007.261 PubMed DOI

Rincon M, Enslen H, Raingeaud J, Recht M, Zapton T, Su MS, Penix LA, Davis RJ, Flavell RA (1998) Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J 17:2817–2829 10.1093/emboj/17.10.2817 PubMed DOI PMC

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47 10.1093/nar/gkv007 PubMed DOI PMC

Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M (2011) Global quantification of mammalian gene expression control. Nature 473:337–342 10.1038/nature10098 PubMed DOI

Sergushichev AA (2016) An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. Preprint at https://www.biorxiv.org/content/10.1101/060012v1 DOI

Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM et al (1992) Rag-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J Rearrangement. Cell 68:855–867 10.1016/0092-8674(92)90029-C PubMed DOI

Shinkawa Y, Imami K, Fuseya Y, Sasaki K, Ohmura K, Ishihama Y, Morinobu A, Iwai K (2022) ABIN1 is a signal-induced autophagy receptor that attenuates NF-kappaB activation by recognizing linear ubiquitin chains. FEBS Lett 596:1147–1164 10.1002/1873-3468.14323 PubMed DOI

Singh N, Maus MV (2023) Synthetic manipulation of the cancer-immunity cycle: CAR-T cell therapy. Immunity 56:2296–2310 10.1016/j.immuni.2023.09.010 PubMed DOI

Sommers CL, Dejarnette JB, Huang K, Lee J, El-Khoury D, Shores EW, Love PE (2000) Function of CD3 epsilon-mediated signals in T cell development. J Exp Med 192:913–919 10.1084/jem.192.6.913 PubMed DOI PMC

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550 10.1073/pnas.0506580102 PubMed DOI PMC

Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S et al (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132 10.1038/ncb1821 PubMed DOI

Tsyklauri O, Chadimova T, Niederlova V, Kovarova J, Michalik J, Malatova I, Janusova S, Ivashchenko O, Rossez H, Drobek A et al (2023) Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2. eLife 12:e79342 10.7554/eLife.79342 PubMed DOI PMC

Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, Mann M, Cox J (2016) The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13:731–740 10.1038/nmeth.3901 PubMed DOI

Van Beek AA, Zhou G, Doukas M, Boor PPC, Noordam L, Mancham S, Campos Carrascosa L, Van Der Heide-Mulder M, Polak WG, Ijzermans JNM et al (2019) GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma. Int J Cancer 145:1111–1124 10.1002/ijc.32181 PubMed DOI PMC

Verstrepen L, Verhelst K, Van Loo G, Carpentier I, Ley SC, Beyaert R (2010) Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem Pharm 80:2009–2020 10.1016/j.bcp.2010.06.044 PubMed DOI

Wortzman ME, Clouthier DL, Mcpherson AJ, Lin GH, Watts TH (2013) The contextual role of TNFR family members in CD8(+) T-cell control of viral infections. Immunol Rev 255:125–148 10.1111/imr.12086 PubMed DOI

Yin H, Karayel O, Chao YY, Seeholzer T, Hamp I, Plettenburg O, Gehring T, Zielinski C, Mann M, Krappmann D (2022) A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-kappaB signaling in activated T cells. Cell Mol Life Sci 79:112 10.1007/s00018-022-04154-z PubMed DOI PMC

Zehn D, Lee SY, Bevan MJ (2009) Complete but curtailed T-cell response to very low-affinity antigen. Nature 458:211–214 10.1038/nature07657 PubMed DOI PMC

Zhao M, Chauhan P, Sherman CA, Singh A, Kaileh M, Mazan-Mamczarz K, Ji H, Joy J, Nandi S, De S et al (2023) NF-kappaB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells. Nat Immunol 24:1552–1564 10.1038/s41590-023-01561-7 PubMed DOI PMC

Zhou J, Wu R, High AA, Slaughter CA, Finkelstein D, Rehg JE, Redecke V, Hacker H (2011) A20-binding inhibitor of NF-kappaB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein beta activation and protects from inflammatory disease. Proc Natl Acad Sci USA 108:E998–E1006 10.1073/pnas.1106232108 PubMed DOI PMC