The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

Adaptive Immunity Group Central European Institute of Technology Brno Czech Republic

Center of Life Sciences Skolkovo Institute of Science and Technology Moscow Russian Federation

Division of Infection and Immunity Cardiff University School of Medicine Cardiff United Kingdom

Faculty of Bioengineering and Bioinformatics Lomonosov Moscow State University Moscow Russian Federation

Genomics of Adaptive Immunity Department Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences Moscow Russian Federation

Institute of Translational Medicine Center for Precision Genome Editing and Genetic Technologies for Biomedicine Pirogov Russian National Research Medical University Moscow Russian Federation

Systems Immunity Research Institute Cardiff University School of Medicine Cardiff United Kingdom

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Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC, Bowerman NA, Chen W, Levin AM, Connolly JM, Zhu C, Kranz DM, Garcia KC. T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity. 2011;35:681–693. doi: 10.1016/j.immuni.2011.09.013. PubMed DOI PMC

Akdis M, Palomares O, van de Veen W, van Splunter M, Akdis CA. Th17 and Th22 cells: a confusion of antimicrobial response with tissue inflammation versus protection. Journal of Allergy and Clinical Immunology. 2012;129:1438–1449. doi: 10.1016/j.jaci.2012.05.003. PubMed DOI

Akkaya B, Oya Y, Akkaya M, Al Souz J, Holstein AH, Kamenyeva O, Kabat J, Matsumura R, Dorward DW, Glass DD, Shevach EM. Regulatory T cells mediate specific suppression by depleting peptide-MHC class II from dendritic cells. Nature Immunology. 2019;20:218–231. doi: 10.1038/s41590-018-0280-2. PubMed DOI PMC

Alabbas SY, Begun J, Florin TH, Oancea I. The role of IL-22 in the resolution of sterile and nonsterile inflammation. Clinical & Translational Immunology. 2018;7:e1017. doi: 10.1002/cti2.1017. PubMed DOI PMC

Allan RS, Zueva E, Cammas F, Schreiber HA, Masson V, Belz GT, Roche D, Maison C, Quivy JP, Almouzni G, Amigorena S. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature. 2012;487:249–253. doi: 10.1038/nature11173. PubMed DOI

Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Filì L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S. Phenotypic and functional features of human Th17 cells. Journal of Experimental Medicine. 2007;204:1849–1861. doi: 10.1084/jem.20070663. PubMed DOI PMC

Arvey A, van der Veeken J, Plitas G, Rich SS, Concannon P, Rudensky AY. Genetic and epigenetic variation in the lineage specification of regulatory T cells. eLife. 2015;4:e07571. doi: 10.7554/eLife.07571. PubMed DOI PMC

Aune TM, Collins PL, Chang S. Epigenetics and T helper 1 differentiation. Immunology. 2009;126:299–305. doi: 10.1111/j.1365-2567.2008.03026.x. PubMed DOI PMC

Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell. 2016;167:1067–1078. doi: 10.1016/j.cell.2016.09.050. PubMed DOI

Bacher P, Scheffold A. Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy. Mucosal Immunology. 2018;11:1537–1550. doi: 10.1038/s41385-018-0038-z. PubMed DOI

Barberis M, Helikar T, Verbruggen P. Simulation of stimulation: cytokine dosage and cell cycle crosstalk driving timing-dependent T cell differentiation. Frontiers in Physiology. 2018;9:879. doi: 10.3389/fphys.2018.00879. PubMed DOI PMC

Baumjohann D, Ansel KM. Tracking early T follicular helper cell differentiation in vivo. Methods in Molecular Biology. 2015;1291:27–38. doi: 10.1007/978-1-4939-2498-1_3. PubMed DOI PMC

Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, Flano E, Mejias A, Albrecht RA, Blankenship D, Xu H, Pascual V, Banchereau J, Garcia-Sastre A, Palucka AK, Ramilo O, Ueno H. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Science Translational Medicine. 2013;5:176ra32. doi: 10.1126/scitranslmed.3005191. PubMed DOI PMC

Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T, Elyaman W, Khoury SJ, Kuchroo VK, Baecher-Allan C, Hafler DA. TGF-β induces IL-9 production from human Th17 cells. Journal of Immunology. 2010;185:46–54. doi: 10.4049/jimmunol.1000356. PubMed DOI PMC

Bolotin DA, Poslavsky S, Mitrophanov I, Shugay M, Mamedov IZ, Putintseva EV, Chudakov DM. MiXCR: software for comprehensive adaptive immunity profiling. Nature Methods. 2015;12:380–381. doi: 10.1038/nmeth.3364. PubMed DOI

Bolotin DA, Poslavsky S, Davydov AN, Frenkel FE, Fanchi L, Zolotareva OI, Hemmers S, Putintseva EV, Obraztsova AS, Shugay M, Ataullakhanov RI, Rudensky AY, Schumacher TN, Chudakov DM. Antigen receptor repertoire profiling from RNA-seq data. Nature Biotechnology. 2017;35:908–911. doi: 10.1038/nbt.3979. PubMed DOI PMC

Bolotin DA, Poslavsky S, Davydov AN, Chudakov DM. Reply to "Evaluation of immune repertoire inference methods from RNA-seq data". Nature Biotechnology. 2018;36:1035–1036. doi: 10.1038/nbt.4296. PubMed DOI

Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D, Smolen JS, Scheinecker C. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE) International Immunology. 2008;20:861–868. doi: 10.1093/intimm/dxn044. PubMed DOI

Booth NJ, McQuaid AJ, Sobande T, Kissane S, Agius E, Jackson SE, Salmon M, Falciani F, Yong K, Rustin MH, Akbar AN, Vukmanovic-Stejic M. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. Journal of Immunology. 2010;184:4317–4326. doi: 10.4049/jimmunol.0903781. PubMed DOI

Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W. CD4+ T cell help in cancer immunology and immunotherapy. Nature Reviews Immunology. 2018;18:635–647. doi: 10.1038/s41577-018-0044-0. PubMed DOI

Brenna E, Davydov AN, Ladell K, McLaren JE, Bonaiuti P, Metsger M, Ramsden JD, Gilbert SC, Lambe T, Price DA, Campion SL, Chudakov DM, Borrow P, McMichael AJ. CD4+ T follicular helper cells in human tonsils and blood are clonally convergent but divergent from non-Tfh CD4+ cells. Cell Reports. 2020;30:137–152. doi: 10.1016/j.celrep.2019.12.016. PubMed DOI PMC

Brown CC, Esterhazy D, Sarde A, London M, Pullabhatla V, Osma-Garcia I, Al-Bader R, Ortiz C, Elgueta R, Arno M, de Rinaldis E, Mucida D, Lord GM, Noelle RJ. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity. 2015;42:499–511. doi: 10.1016/j.immuni.2015.02.003. PubMed DOI PMC

Chakrabarti P, Bhattacharyya R. Geometry of nonbonded interactions involving planar groups in proteins. Progress in Biophysics and Molecular Biology. 2007;95:83–137. doi: 10.1016/j.pbiomolbio.2007.03.016. PubMed DOI

Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nature Medicine. 2011;17:983–988. doi: 10.1038/nm.2426. PubMed DOI PMC

Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK. Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. Journal of Immunology. 2011;187:5615–5626. doi: 10.4049/jimmunol.1101058. PubMed DOI

Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annual Review of Immunology. 1997;15:297–322. doi: 10.1146/annurev.immunol.15.1.297. PubMed DOI

Cook MC, Tangye SG. Primary immune deficiencies affecting lymphocyte differentiation: lessons from the spectrum of resulting infections. International Immunology. 2009;21:1003–1011. doi: 10.1093/intimm/dxp076. PubMed DOI

Corse E, Gottschalk RA, Allison JP. Strength of TCR-peptide/MHC interactions and in vivo T cell responses. Journal of Immunology. 2011;186:5039–5045. doi: 10.4049/jimmunol.1003650. PubMed DOI

Costa N, Marques O, Godinho SI, Carvalho C, Leal B, Figueiredo AM, Vasconcelos C, Marinho A, Moraes-Fontes MF, Gomes da Costa A, Ponte C, Campanilho-Marques R, Cóias T, Martins AR, Viana JF, Lima M, Martins B, Fesel C. Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives. Clinical & Experimental Immunology. 2017;189:318–330. doi: 10.1111/cei.12991. PubMed DOI PMC

Coutinho A, Caramalho I, Seixas E, Demengeot J. Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. Current Topics in Microbiology and Immunology. 2005;293:43–71. doi: 10.1007/3-540-27702-1_3. PubMed DOI

Darrigues J, van Meerwijk JPM, Romagnoli P. Age-dependent changes in regulatory T lymphocyte development and function: a mini-review. Gerontology. 2018;64:28–35. doi: 10.1159/000478044. PubMed DOI

Davydov AN, Obraztsova AS, Lebedin MY, Turchaninova MA, Staroverov DB, Merzlyak EM, Sharonov GV, Kladova O, Shugay M, Britanova OV, Chudakov DM. Comparative analysis of B-cell receptor repertoires induced by live yellow fever vaccine in young and middle-age donors. Frontiers in Immunology. 2018;9:2309. doi: 10.3389/fimmu.2018.02309. PubMed DOI PMC

De Simone G, Mazza EMC, Cassotta A, Davydov AN, Kuka M, Zanon V, De Paoli F, Scamardella E, Metsger M, Roberto A, Pilipow K, Colombo FS, Tenedini E, Tagliafico E, Gattinoni L, Mavilio D, Peano C, Price DA, Singh SP, Farber JM, Serra V, Cucca F, Ferrari F, Orrù V, Fiorillo E, Iannacone M, Chudakov DM, Sallusto F, Lugli E. CXCR3 identifies human naive CD8+ T cells with enhanced effector differentiation potential. Journal of Immunology. 2019;203:3179–3189. doi: 10.4049/jimmunol.1901072. PubMed DOI PMC

Duhen T, Campbell DJ. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. Journal of Immunology. 2014;193:120–129. doi: 10.4049/jimmunol.1302734. PubMed DOI PMC

DuPage M, Bluestone JA. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nature Reviews Immunology. 2016;16:149–163. doi: 10.1038/nri.2015.18. PubMed DOI

Egorov ES, Merzlyak EM, Shelenkov AA, Britanova OV, Sharonov GV, Staroverov DB, Bolotin DA, Davydov AN, Barsova E, Lebedev YB, Shugay M, Chudakov DM. Quantitative profiling of immune repertoires for minor lymphocyte counts using unique molecular identifiers. Journal of Immunology. 2015;194:6155–6163. doi: 10.4049/jimmunol.1500215. PubMed DOI

Egorov ES, Kasatskaya SA, Zubov VN, Izraelson M, Nakonechnaya TO, Staroverov DB, Angius A, Cucca F, Mamedov IZ, Rosati E, Franke A, Shugay M, Pogorelyy MV, Chudakov DM, Britanova OV. The changing landscape of naive T cell receptor repertoire with human aging. Frontiers in Immunology. 2018;9:1618. doi: 10.3389/fimmu.2018.01618. PubMed DOI PMC

Eisenbarth SC. Dendritic cell subsets in T cell programming: location dictates function. Nature Reviews Immunology. 2019;19:89–103. doi: 10.1038/s41577-018-0088-1. PubMed DOI PMC

Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, Durham SR, Schmidt-Weber CB, Cavani A. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. Journal of Clinical Investigation. 2009;119:3573–3585. doi: 10.1172/JCI40202. PubMed DOI PMC

Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nature Immunology. 2009a;10:375–384. doi: 10.1038/ni.1704. PubMed DOI PMC

Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity. 2009b;30:324–335. doi: 10.1016/j.immuni.2009.03.003. PubMed DOI PMC

Feng Y, van der Veeken J, Shugay M, Putintseva EV, Osmanbeyoglu HU, Dikiy S, Hoyos BE, Moltedo B, Hemmers S, Treuting P, Leslie CS, Chudakov DM, Rudensky AY. A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance. Nature. 2015;528:132–136. doi: 10.1038/nature16141. PubMed DOI PMC

Fink PJ. The biology of recent thymic emigrants. Annual Review of Immunology. 2013;31:31–50. doi: 10.1146/annurev-immunol-032712-100010. PubMed DOI

Finotto S. T-cell regulation in asthmatic diseases. Chemical Immunology and Allergy. 2008;94:83–92. doi: 10.1159/000154869. PubMed DOI

Gartlan KH, Bommiasamy H, Paz K, Wilkinson AN, Owen M, Reichenbach DK, Banovic T, Wehner K, Buchanan F, Varelias A, Kuns RD, Chang K, Fedoriw Y, Shea T, Coghill J, Zaiken M, Plank MW, Foster PS, Clouston AD, Blazar BR, Serody JS, Hill GR. A critical role for donor-derived IL-22 in cutaneous chronic GVHD. American Journal of Transplantation. 2018;18:810–820. doi: 10.1111/ajt.14513. PubMed DOI PMC

Geginat J, Paroni M, Maglie S, Alfen JS, Kastirr I, Gruarin P, De Simone M, Pagani M, Abrignani S. Plasticity of human CD4 T cell subsets. Frontiers in Immunology. 2014;5:630. doi: 10.3389/fimmu.2014.00630. PubMed DOI PMC

Grimsholm O, Piano Mortari E, Davydov AN, Shugay M, Obraztsova AS, Bocci C, Marasco E, Marcellini V, Aranburu A, Farroni C, Silvestris DA, Cristofoletti C, Giorda E, Scarsella M, Cascioli S, Barresi S, Lougaris V, Plebani A, Cancrini C, Finocchi A, Moschese V, Valentini D, Vallone C, Signore F, de Vincentiis G, Zaffina S, Russo G, Gallo A, Locatelli F, Tozzi AE, Tartaglia M, Chudakov DM, Carsetti R. The interplay between CD27dull and CD27bright B cells ensures the flexibility, stability, and resilience of human B cell memory. Cell Reports. 2020;30:2963–2977. doi: 10.1016/j.celrep.2020.02.022. PubMed DOI

Groom JR, Richmond J, Murooka TT, Sorensen EW, Sung JH, Bankert K, von Andrian UH, Moon JJ, Mempel TR, Luster AD. CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity. 2012;37:1091–1103. doi: 10.1016/j.immuni.2012.08.016. PubMed DOI PMC

Häringer B, Lozza L, Steckel B, Geginat J. Identification and characterization of IL-10/IFN-γ-producing effector-like T cells with regulatory function in human blood. Journal of Experimental Medicine. 2009;206:1009–1017. doi: 10.1084/jem.20082238. PubMed DOI PMC

Hegazy AN, Peine M, Helmstetter C, Panse I, Fröhlich A, Bergthaler A, Flatz L, Pinschewer DD, Radbruch A, Löhning M. Interferons direct Th2 cell reprogramming to generate a stable GATA-3+T-bet+ cell subset with combined Th2 and Th1 cell functions. Immunity. 2010;32:116–128. doi: 10.1016/j.immuni.2009.12.004. PubMed DOI

Heinemann C, Heink S, Petermann F, Vasanthakumar A, Rothhammer V, Doorduijn E, Mitsdoerffer M, Sie C, Prazeres da Costa O, Buch T, Hemmer B, Oukka M, Kallies A, Korn T. IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nature Communications. 2014;5:3770. doi: 10.1038/ncomms4770. PubMed DOI

Hernández-Santos N, Huppler AR, Peterson AC, Khader SA, McKenna KC, Gaffen SL. Th17 cells confer long-term adaptive immunity to oral mucosal Candida albicans infections. Mucosal Immunology. 2013;6:900–910. doi: 10.1038/mi.2012.128. PubMed DOI PMC

Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B. Fate mapping of IL-17-producing T cells in inflammatory responses. Nature Immunology. 2011;12:255–263. doi: 10.1038/ni.1993. PubMed DOI PMC

Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, Edinger M. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108:4260–4267. doi: 10.1182/blood-2006-06-027409. PubMed DOI

Hoffmann T, Krackhardt AM, Antes I. Quantitative analysis of the association angle between T-cell receptor Vα/Vβ domains reveals important features for epitope recognition. PLOS Computational Biology. 2015;11:e1004244. doi: 10.1371/journal.pcbi.1004244. PubMed DOI PMC

Izraelson M, Nakonechnaya TO, Moltedo B, Egorov ES, Kasatskaya SA, Putintseva EV, Mamedov IZ, Staroverov DB, Shemiakina II, Zakharova MY, Davydov AN, Bolotin DA, Shugay M, Chudakov DM, Rudensky AY, Britanova OV. Comparative analysis of murine T-cell receptor repertoires. Immunology. 2018;153:133–144. doi: 10.1111/imm.12857. PubMed DOI PMC

Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunology. 2001;2:301–306. doi: 10.1038/86302. PubMed DOI

Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I, Lord GM, Jenner RG. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nature Communications. 2012;3:1268. doi: 10.1038/ncomms2260. PubMed DOI PMC

Kidera A, Konishi Y, Oka M, Ooi T, Scheraga HA. Statistical analysis of the physical properties of the 20 naturally occurring amino acids. Journal of Protein Chemistry. 1985;4:23–55. doi: 10.1007/BF01025492. DOI

Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, Phair J, Jamieson BD. Homeostasis of the naive CD4+ T cell compartment during aging. Journal of Immunology. 2008;180:1499–1507. doi: 10.4049/jimmunol.180.3.1499. PubMed DOI PMC

Kosmrlj A, Jha AK, Huseby ES, Kardar M, Chakraborty AK. How the thymus designs antigen-specific and self-tolerant T cell receptor sequences. PNAS. 2008;105:16671–16676. doi: 10.1073/pnas.0808081105. PubMed DOI PMC

Kosmrlj A, Read EL, Qi Y, Allen TM, Altfeld M, Deeks SG, Pereyra F, Carrington M, Walker BD, Chakraborty AK. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature. 2010;465:350–354. doi: 10.1038/nature08997. PubMed DOI PMC

Krebs CF, Steinmetz OM. CD4+ T cell fate in glomerulonephritis: a tale of Th1, Th17, and novel Treg subtypes. Mediators of Inflammation. 2016;2016:5393894. doi: 10.1155/2016/5393894. PubMed DOI PMC

Kreiter S, Vormehr M, van de Roemer N, Diken M, Löwer M, Diekmann J, Boegel S, Schrörs B, Vascotto F, Castle JC, Tadmor AD, Schoenberger SP, Huber C, Türeci Ö, Sahin U. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520:692–696. doi: 10.1038/nature14426. PubMed DOI PMC

Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh C-S. Antigen-specific peripheral shaping of the natural regulatory T cell population. Journal of Experimental Medicine. 2008;205:3105–3117. doi: 10.1084/jem.20081359. PubMed DOI PMC

Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107. doi: 10.1016/j.immuni.2008.11.005. PubMed DOI PMC

Lei H, Kuchenbecker L, Streitz M, Sawitzki B, Vogt K, Landwehr-Kenzel S, Millward J, Juelke K, Babel N, Neumann A, Reinke P, Volk HD. Human CD45RA− FoxP3hi memory-type regulatory T cells show distinct TCR repertoires with conventional T cells and play an important role in controlling early immune activation. American Journal of Transplantation. 2015;15:2625–2635. doi: 10.1111/ajt.13315. PubMed DOI

Leipe J, Pirronello F, Klose A, Schulze-Koops H, Skapenko A. Increased plasticity of non-classic Th1 cells toward the Th17 phenotype. Modern Rheumatology. 2020;30:930–936. doi: 10.1080/14397595.2019.1667473. PubMed DOI

Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nature Immunology. 2014;15:1070–1078. doi: 10.1038/ni.3004. PubMed DOI PMC

Li MO, Rudensky AY. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nature Reviews Immunology. 2016;16:220–233. doi: 10.1038/nri.2016.26. PubMed DOI PMC

Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG. Foxp3+ follicular regulatory T cells control the germinal center response. Nature Medicine. 2011;17:975–982. doi: 10.1038/nm.2425. PubMed DOI PMC

Logunova NN, Kriukova VV, Shelyakin PV, Egorov ES, Pereverzeva A, Bozhanova NG, Shugay M, Shcherbinin DS, Pogorelyy MV, Merzlyak EM, Zubov VN, Meiler J, Chudakov DM, Apt AS, Britanova OV. MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4+ T cells. PNAS. 2020;117:13659–13669. doi: 10.1073/pnas.2003170117. PubMed DOI PMC

Maceiras AR, Almeida SCP, Mariotti-Ferrandiz E, Chaara W, Jebbawi F, Six A, Hori S, Klatzmann D, Faro J, Graca L. T follicular helper and T follicular regulatory cells have different TCR specificity. Nature Communications. 2017;8:15067. doi: 10.1038/ncomms15067. PubMed DOI PMC

Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, Cimaz R, De Palma R, Liotta F, Maggi E, Romagnani S, Cosmi L, Annunziato F. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. European Journal of Immunology. 2012;42:3180–3188. doi: 10.1002/eji.201242648. PubMed DOI

Marks BR, Nowyhed HN, Choi JY, Poholek AC, Odegard JM, Flavell RA, Craft J. Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation. Nature Immunology. 2009;10:1125–1132. doi: 10.1038/ni.1783. PubMed DOI PMC

Martin J, Lavery R. Arbitrary protein-protein docking targets biologically relevant interfaces. BMC Biophysics. 2012;5:7. doi: 10.1186/2046-1682-5-7. PubMed DOI PMC

McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, Hoffmüller U, Baron U, Olek S, Bluestone JA, Brusko TM. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. Journal of Immunology. 2011;186:3918–3926. doi: 10.4049/jimmunol.1003099. PubMed DOI PMC

McDonald DR. TH17 deficiency in human disease. Journal of Allergy and Clinical Immunology. 2012;129:1429–1435. doi: 10.1016/j.jaci.2012.03.034. PubMed DOI PMC

McGee HS, Agrawal DK. TH2 cells in the pathogenesis of airway remodeling: regulatory T cells a plausible Panacea for asthma. Immunologic Research. 2006;35:219–232. doi: 10.1385/IR:35:3:219. PubMed DOI

Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human Th1 and Th2 lymphocytes. Nature Immunology. 2003;4:78–86. doi: 10.1038/ni872. PubMed DOI

Misiak A, Leuzzi R, Allen AC, Galletti B, Baudner BC, D'Oro U, O'Hagan DT, Pizza M, Seubert A, Mills KHG. Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model. Vaccine. 2017;35:5256–5263. doi: 10.1016/j.vaccine.2017.08.009. PubMed DOI

Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012;36:262–275. doi: 10.1016/j.immuni.2011.12.012. PubMed DOI

Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Nochy D, Debré P, Piette JC, Gorochov G. Global natural regulatory T cell depletion in active systemic lupus erythematosus. Journal of Immunology. 2005;175:8392–8400. doi: 10.4049/jimmunol.175.12.8392. PubMed DOI

Miyazaki Y, Nakayamada S, Kubo S, Nakano K, Iwata S, Miyagawa I, Ma X, Trimova G, Sakata K, Tanaka Y. Th22 cells promote osteoclast differentiation via production of IL-22 in rheumatoid arthritis. Frontiers in Immunology. 2018;9:2901. doi: 10.3389/fimmu.2018.02901. PubMed DOI PMC

Miyazawa S, Jernigan RL. Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. Journal of Molecular Biology. 1996;256:623–644. doi: 10.1006/jmbi.1996.0114. PubMed DOI

Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34:108–121. doi: 10.1016/j.immuni.2010.12.012. PubMed DOI PMC

Mosmann TR, Coffman RL. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. PubMed DOI

Muranski P, Restifo NP. Essentials of Th17 cell commitment and plasticity. Blood. 2013;121:2402–2414. doi: 10.1182/blood-2012-09-378653. PubMed DOI PMC

Murphy E, Shibuya K, Hosken N, Openshaw P, Maino V, Davis K, Murphy K, O'Garra A. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. Journal of Experimental Medicine. 1996;183:901–913. doi: 10.1084/jem.183.3.901. PubMed DOI PMC

Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nature Immunology. 2010;11:674–680. doi: 10.1038/ni.1899. PubMed DOI PMC

Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37:785–799. doi: 10.1016/j.immuni.2012.09.010. PubMed DOI

Osnes LT, Nakken B, Bodolay E, Szodoray P. Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies — novel tool for diagnostics and patient follow-up. Autoimmunity Reviews. 2013;12:967–971. doi: 10.1016/j.autrev.2013.02.003. PubMed DOI

Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology. 2008;125:450–458. doi: 10.1111/j.1365-2567.2008.02992.x. PubMed DOI PMC

Panzer M, Sitte S, Wirth S, Drexler I, Sparwasser T, Voehringer D. Rapid in vivo conversion of effector T cells into Th2 cells during helminth infection. Journal of Immunology. 2012;188:615–623. doi: 10.4049/jimmunol.1101164. PubMed DOI

Plank MW, Kaiko GE, Maltby S, Weaver J, Tay HL, Shen W, Wilson MS, Durum SK, Foster PS. Th22 cells form a distinct Th lineage from Th17 cells in vitro with unique transcriptional properties and Tbet-dependent Th1 plasticity. Journal of Immunology. 2017;198:2182–2190. doi: 10.4049/jimmunol.1601480. PubMed DOI PMC

Protti MP, De Monte L, Di Lullo G. Tumor antigen-specific CD4+ T cells in Cancer immunity: from antigen identification to tumor prognosis and development of therapeutic strategies. Tissue Antigens. 2014;83:237–246. doi: 10.1111/tan.12329. PubMed DOI

Puniya BL, Todd RG, Mohammed A, Brown DM, Barberis M, Helikar T. A mechanistic computational model reveals that plasticity of CD4+ T cell differentiation is a function of cytokine composition and dosage. Frontiers in Physiology. 2018;9:878. doi: 10.3389/fphys.2018.00878. PubMed DOI PMC

Rivino L, Messi M, Jarrossay D, Lanzavecchia A, Sallusto F, Geginat J. Chemokine receptor expression identifies pre-T helper (Th)1, pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. Journal of Experimental Medicine. 2004;200:725–735. doi: 10.1084/jem.20040774. PubMed DOI PMC

Rolla S, Bardina V, De Mercanti S, Quaglino P, De Palma R, Gned D, Brusa D, Durelli L, Novelli F, Clerico M. Th22 cells are expanded in multiple sclerosis and are resistant to IFN-β. Journal of Leukocyte Biology. 2014;96:1155–1164. doi: 10.1189/jlb.5A0813-463RR. PubMed DOI

Ryba-Stanisławowska M, Werner P, Brandt A, Myśliwiec M, Myśliwska J. Th9 and Th22 immune response in young patients with type 1 diabetes. Immunologic Research. 2016;64:730–735. doi: 10.1007/s12026-015-8765-7. PubMed DOI

Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. Journal of Immunology. 1994;153:3514–3522. PubMed

Sallusto F. Heterogeneity of human CD4+ T cells against microbes. Annual Review of Immunology. 2016;34:317–334. doi: 10.1146/annurev-immunol-032414-112056. PubMed DOI

Sawant DV, Vignali DA. Once a Treg, always a Treg? Immunological Reviews. 2014;259:173–191. doi: 10.1111/imr.12173. PubMed DOI PMC

Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE, Campbell L, Yawalkar N, Kupper TS, Clark RA. Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Science Translational Medicine. 2014;6:219ra8. doi: 10.1126/scitranslmed.3007828. PubMed DOI PMC

Shugay M, Britanova OV, Merzlyak EM, Turchaninova MA, Mamedov IZ, Tuganbaev TR, Bolotin DA, Staroverov DB, Putintseva EV, Plevova K, Linnemann C, Shagin D, Pospisilova S, Lukyanov S, Schumacher TN, Chudakov DM. Towards error-free profiling of immune repertoires. Nature Methods. 2014;11:653–655. doi: 10.1038/nmeth.2960. PubMed DOI

Shugay M, Bagaev DV, Turchaninova MA, Bolotin DA, Britanova OV, Putintseva EV, Pogorelyy MV, Nazarov VI, Zvyagin IV, Kirgizova VI, Kirgizov KI, Skorobogatova EV, Chudakov DM. VDJtools: unifying post-analysis of T cell receptor repertoires. PLOS Computational Biology. 2015;11:e1004503. doi: 10.1371/journal.pcbi.1004503. PubMed DOI PMC

Shulman Z, Gitlin AD, Targ S, Jankovic M, Pasqual G, Nussenzweig MC, Victora GD. T follicular helper cell dynamics in germinal centers. Science. 2013;341:673–677. doi: 10.1126/science.1241680. PubMed DOI PMC

Sibener LV, Fernandes RA, Kolawole EM, Carbone CB, Liu F, McAffee D, Birnbaum ME, Yang X, Su LF, Yu W, Dong S, Gee MH, Jude KM, Davis MM, Groves JT, Goddard WA, Heath JR, Evavold BD, Vale RD, Garcia KC. Isolation of a structural mechanism for uncoupling T cell receptor signaling from peptide-MHC binding. Cell. 2018;174:672–687. doi: 10.1016/j.cell.2018.06.017. PubMed DOI PMC

Silva SL, Albuquerque AS, Serra-Caetano A, Foxall RB, Pires AR, Matoso P, Fernandes SM, Ferreira J, Cheynier R, Victorino RM, Caramalho I, Barata JT, Sousa AE. Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7. Oncotarget. 2016;7:12163–12175. doi: 10.18632/oncotarget.7512. PubMed DOI PMC

Spence A, Purtha W, Tam J, Dong S, Kim Y, Ju CH, Sterling T, Nakayama M, Robinson WH, Bluestone JA, Anderson MS, Tang Q. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. PNAS. 2018;115:5265–5270. doi: 10.1073/pnas.1715590115. PubMed DOI PMC

Stadinski BD, Shekhar K, Gómez-Touriño I, Jung J, Sasaki K, Sewell AK, Peakman M, Chakraborty AK, Huseby ES. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nature Immunology. 2016;17:946–955. doi: 10.1038/ni.3491. PubMed DOI PMC

Su LF, Del Alcazar D, Stelekati E, Wherry EJ, Davis MM. Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood. PNAS. 2016;113:E6192–E6198. doi: 10.1073/pnas.1611723113. PubMed DOI PMC

Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28:687–697. doi: 10.1016/j.immuni.2008.03.016. PubMed DOI PMC

Thiault N, Darrigues J, Adoue V, Gros M, Binet B, Perals C, Leobon B, Fazilleau N, Joffre OP, Robey EA, van Meerwijk JP, Romagnoli P. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nature Immunology. 2015;16:628–634. doi: 10.1038/ni.3150. PubMed DOI

Tulic MK, Andrews D, Crook ML, Charles A, Tourigny MR, Moqbel R, Prescott SL. Changes in thymic regulatory T-cell maturation from birth to puberty: differences in atopic children. Journal of Allergy and Clinical Immunology. 2012;129:199–206. doi: 10.1016/j.jaci.2011.10.016. PubMed DOI

Vella LA, Buggert M, Manne S, Herati RS, Sayin I, Kuri-Cervantes L, Bukh Brody I, O’Boyle KC, Kaprielian H, Giles JR, Nguyen S, Muselman A, Antel JP, Bar-Or A, Johnson ME, Canaday DH, Naji A, Ganusov VV, Laufer TM, Wells AD, Dori Y, Itkin MG, Betts MR, Wherry EJ. T follicular helper cells in human efferent lymph retain lymphoid characteristics. Journal of Clinical Investigation. 2019;129:3185–3200. doi: 10.1172/JCI125628. PubMed DOI PMC

Vinuesa CG, Linterman MA, Yu D, MacLennan IC. Follicular helper T cells. Annual Review of Immunology. 2016;34:335–368. doi: 10.1146/annurev-immunol-041015-055605. PubMed DOI

Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, Bover L, Hanabuchi S, Khalili J, Marinova E, Zheng B, Littman DR, Liu YJ. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. PNAS. 2009;106:4793–4798. doi: 10.1073/pnas.0900408106. PubMed DOI PMC

Vroman H, van den Blink B, Kool M. Mode of dendritic cell activation: the decisive hand in Th2/Th17 cell differentiation. Implications in asthma severity? Immunobiology. 2015;220:254–261. doi: 10.1016/j.imbio.2014.09.016. PubMed DOI

Waickman AT, Ligons DL, Hwang S, Park JY, Lazarevic V, Sato N, Hong C, Park JH. CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans. Cytokine. 2017;99:266–274. doi: 10.1016/j.cyto.2017.08.004. PubMed DOI PMC

Walker LS, von Herrath M. CD4 T cell differentiation in type 1 diabetes. Clinical & Experimental Immunology. 2016;183:16–29. doi: 10.1111/cei.12672. PubMed DOI PMC

Wang JH, Reinherz EL. The structural basis of αβ T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunological Reviews. 2012;250:102–119. doi: 10.1111/j.1600-065X.2012.01161.x. PubMed DOI PMC

Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC, Sharma P, Wang J, Wargo JA, Pe'er D, Allison JP. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170:1120–1133. doi: 10.1016/j.cell.2017.07.024. PubMed DOI PMC

Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44–56. doi: 10.1016/j.immuni.2008.05.007. PubMed DOI PMC

Yang BH, Wang K, Wan S, Liang Y, Yuan X, Dong Y, Cho S, Xu W, Jepsen K, Feng GS, Lu LF, Xue HH, Fu W. TCF1 and LEF1 control Treg competitive survival and Tfr development to prevent autoimmune diseases. Cell Reports. 2019;27:3629–3645. doi: 10.1016/j.celrep.2019.05.061. PubMed DOI PMC

Zhou X, Bailey-Bucktrout S, Jeker LT, Bluestone JA. Plasticity of CD4+ FoxP3+ T cells. Current Opinion in Immunology. 2009a;21:281–285. doi: 10.1016/j.coi.2009.05.007. PubMed DOI PMC

Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009b;30:646–655. doi: 10.1016/j.immuni.2009.05.001. PubMed DOI

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annual Review of Immunology. 2010;28:445–489. doi: 10.1146/annurev-immunol-030409-101212. PubMed DOI PMC

Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanzavecchia A, Sallusto F. Pathogen-induced human TH17 cells produce IFNγ or IL-10 and are regulated by IL-1β. Nature. 2012;484:514–518. doi: 10.1038/nature10957. PubMed DOI

Aberrant adaptive immune response underlies genetic susceptibility to tuberculosis

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