Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czechia

Faculty of Science Department of Cell Biology Charles University Prague Czechia

Institute for Medical Microbiology Immunology and Hygiene Technical University of Munich Munich Germany

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

Laboratory of Gnotobiology Institute of Microbiology of the Czech Academy of Sciences Novy Hradek Czechia

Laboratory of Immunity and Cell Communication BIOCEV 1st Faculty of Medicine Charles University Vestec Czechia

Mikrobiologisches Institut Klinische Mikrobiologie Immunologie und Hygiene Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Zobrazit více v PubMed

Zehn D, Lee SY, Bevan MJ. Complete but curtailed T cell response to very low affinity antigen. Nature (2009) 458(7235):211–4. doi: 10.1038/nature07657 PubMed DOI PMC

King CG, Koehli S, Hausmann B, Schmaler M, Zehn D, Palmer E. T Cell affinity regulates asymmetric division, effector cell differentiation, and tissue pathology. Immunity (2012) 37(4):709–20. doi: 10.1016/j.immuni.2012.06.021 PubMed DOI PMC

Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, et al. . Thymic selection threshold defined by compartmentalization of Ras/Mapk signalling. Nature (2006) 444(7120):724–9. doi: 10.1038/nature05269 PubMed DOI

Horkova V, Drobek A, Mueller D, Gubser C, Niederlova V, Wyss L, et al. . Dynamics of the coreceptor-lck interactions during T cell development shape the self-reactivity of peripheral Cd4 and Cd8 T cells. Cell Rep (2020) 30(5):1504–14. doi: 10.1016/j.celrep.2020.01.008 PubMed DOI PMC

Stritesky GL, Jameson SC, Hogquist KA. Selection of self-reactive T cells in the thymus. Annu Rev Immunol (2012) 30:95–114. doi: 10.1146/annurev-immunol-020711-075035 PubMed DOI PMC

Paprckova D, Stepanek O. Narcissistic T cells: Reactivity to self makes a difference. FEBS J (2021) 288(6):1778–88. doi: 10.1111/febs.15498 PubMed DOI

Persaud SP, Parker CR, Lo WL, Weber KS, Allen PM. Intrinsic Cd4(+) T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and mhc. Nat Immunol (2014) 15(3):266–74. doi: 10.1038/ni.2822 PubMed DOI PMC

Weber KS, Li QJ, Persaud SP, Campbell JD, Davis MM, Allen PM. Distinct Cd4(+) helper T cells involved in primary and secondary responses to infection. P Natl Acad Sci USA (2012) 109(24):9511–6. doi: 10.1073/pnas.1202408109 PubMed DOI PMC

Fulton RB, Hamilton SE, Xing Y, Best JA, Goldrath AW, Hogquist KA, et al. . The tcr's sensitivity to self peptide-mhc dictates the ability of naive Cd8(+) T cells to respond to foreign antigens. Nat Immunol (2015) 16(1):107–17. doi: 10.1038/ni.3043 PubMed DOI PMC

Swee LK, Tan ZW, Sanecka A, Yoshida N, Patel H, Grotenbreg G, et al. . Peripheral self-reactivity regulates antigen-specific Cd8 T-cell responses and cell division under physiological conditions. Open Biol (2016) 6(11):160293. doi: 10.1098/rsob.160293 PubMed DOI PMC

Drobek A, Moudra A, Mueller D, Huranova M, Horkova V, Pribikova M, et al. . Strong homeostatic tcr signals induce formation of self-tolerant virtual memory Cd8 T cells. EMBO J (2018) 37:e98518. doi: 10.15252/embj.201798518 PubMed DOI PMC

White JT, Cross EW, Burchill MA, Danhorn T, McCarter MD, Rosen HR, et al. . Virtual memory T cells develop and mediate bystander protective immunity in an il-15-Dependent manner. Nat Commun (2016) 7:1–13. doi: 10.1038/ncomms11291 PubMed DOI PMC

Haluszczak C, Akue AD, Hamilton SE, Johnson LD, Pujanauski L, Teodorovic L, et al. . The antigen-specific Cd8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J Exp Med (2009) 206(2):435–48. doi: 10.1084/jem.20081829 PubMed DOI PMC

Moudra A, Niederlova V, Novotny J, Schmiedova L, Kubovciak J, Matejkova T, et al. . Phenotypic and clonal stability of antigen-inexperienced memory-like T cells across the genetic background, hygienic status, and aging. J Immunol (2021) 206(9):2109–21. doi: 10.4049/jimmunol.2001028 PubMed DOI PMC

Miller CH, Klawon DEJ, Zeng S, Lee V, Socci ND, Savage PA. Eomes identifies thymic precursors of self-specific memory-phenotype Cd8(+) T cells. Nat Immunol (2020) 21(5):567–77. doi: 10.1038/s41590-020-0653-1 PubMed DOI PMC

Ju YJ, Lee SW, Kye YC, Lee GW, Kim HO, Yun CH, et al. . Self-reactivity controls functional diversity of naive Cd8(+) T cells by Co-opting tonic type I interferon. Nat Commun (2021) 12(1):6059. doi: 10.1038/s41467-021-26351-3 PubMed DOI PMC

Martinet V, Tonon S, Torres D, Azouz A, Nguyen M, Kohler A, et al. . Type I interferons regulate eomesodermin expression and the development of unconventional memory Cd8(+) T cells. Nat Commun (2015) 6:7089. doi: 10.1038/ncomms8089 PubMed DOI PMC

Wang XF, Shen XR, Chen S, Liu HY, Hong N, Zhong HB, et al. . Reinvestigation of classic T cell subsets and identification of novel cell subpopulations by single-cell rna sequencing. J Immunol (2022) 208(2):396–406. doi: 10.4049/jimmunol.2100581 PubMed DOI

Goldrath AW, Luckey CJ, Park R, Benoist C, Mathis D. The molecular program induced in T cells undergoing homeostatic proliferation. Proc Natl Acad Sci U.S.A. (2004) 101(48):16885–90. doi: 10.1073/pnas.0407417101 PubMed DOI PMC

Luckey CJ, Bhattacharya D, Goldrath AW, Weissman IL, Benoist C, Mathis D. Memory T and memory b cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proc Natl Acad Sci U.S.A. (2006) 103(9):3304–9. doi: 10.1073/pnas.0511137103 PubMed DOI PMC

Zheng L, Qin S, Si W, Wang A, Xing B, Gao R, et al. . Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science (2021) 374(6574):abe6474. doi: 10.1126/science.abe6474 PubMed DOI

Chiu BC, Martin BE, Stolberg VR, Chensue SW. Cutting edge: Central memory Cd8 T cells in aged mice are virtual memory cells. J Immunol (2013) 191(12):5793–6. doi: 10.4049/jimmunol.1302509 PubMed DOI PMC

Renkema KR, Li G, Wu A, Smithey MJ, Nikolich-Zugich J. Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J Immunol (2014) 192(1):151–9. doi: 10.4049/jimmunol.1301453 PubMed DOI PMC

Palmer E, Drobek A, Stepanek O. Opposing effects of actin signaling and lfa-1 on establishing the affinity threshold for inducing effector T-cell responses in mice. Eur J Immunol (2016) 46(8):1887–901. doi: 10.1002/eji.201545909 PubMed DOI

Schober K, Voit F, Grassmann S, Muller TR, Eggert J, Jarosch S, et al. . Reverse tcr repertoire evolution toward dominant low-affinity clones during chronic cmv infection. Nat Immunol (2020) 21(4):434–41. doi: 10.1038/s41590-020-0628-2 PubMed DOI

Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, et al. . Regulation of Cd8+ T cell development by thymus-specific proteasomes. Science (2007) 316(5829):1349–53. doi: 10.1126/science.1141915 PubMed DOI

Xing Y, Jameson SC, Hogquist KA. Thymoproteasome subunit-Beta5t generates peptide-mhc complexes specialized for positive selection. Proc Natl Acad Sci U.S.A. (2013) 110(17):6979–84. doi: 10.1073/pnas.1222244110 PubMed DOI PMC

Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, Ishimaru N, et al. . Thymoproteasome shapes immunocompetent repertoire of Cd8+ T cells. Immunity (2010) 32(1):29–40. doi: 10.1016/j.immuni.2009.10.009 PubMed DOI

Bartleson JM, Viehmann Milam AA, Donermeyer DL, Horvath S, Xia Y, Egawa T, et al. . Strength of tonic T cell receptor signaling instructs T follicular helper cell-fate decisions. Nat Immunol (2020) 21(11):1384–96. doi: 10.1038/s41590-020-0781-7 PubMed DOI PMC

Kwesi-Maliepaard EM, Jacobs H, van Leeuwen F. Signals for antigen-independent differentiation of memory Cd8(+) T cells. Cell Mol Life Sci (2021) 78(19-20):6395–408. doi: 10.1007/s00018-021-03912-9 PubMed DOI PMC

Schaupp L, Muth S, Rogell L, Kofoed-Branzk M, Melchior F, Lienenklaus S, et al. . Microbiota-induced type I interferons instruct a poised basal state of dendritic cells. Cell (2020) 181(5):1080–+. doi: 10.1016/j.cell.2020.04.022 PubMed DOI

Mandl JN, Monteiro JP, Vrisekoop N, Germain RN. T Cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity (2013) 38(2):263–74. doi: 10.1016/j.immuni.2012.09.011 PubMed DOI PMC

Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D, Hermanova P, et al. . Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science (2016) 351(6275):854–7. doi: 10.1126/science.aad8588 PubMed DOI

Shen FW, Saga Y, Litman G, Freeman G, Tung JS, Cantor H, et al. . Cloning of ly-5 cdna. Proc Natl Acad Sci U.S.A. (1985) 82(21):7360–3. doi: 10.1073/pnas.82.21.7360 PubMed DOI PMC

Kurts C, Miller JFAP, Subramaniam RM, Carbone FR, Heath WR. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med (1998) 188(2):409–14. doi: 10.1084/jem.188.2.409 PubMed DOI PMC

Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. T-Cell receptor antagonist peptides induce positive selection. Cell (1994) 76(1):17–27. doi: 10.1016/0092-8674(94)90169-4 PubMed DOI

Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, et al. . Rag-2-Deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell (1992) 68(5):855–67. doi: 10.1016/0092-8674(92)90029-c PubMed DOI

Fink PJ, Swan K, Turk G, Moore MW, Carbone FR. Both intrathymic and peripheral selection modulate the differential expression of V-Beta-5 among Cd4+ and Cd8+ T-cells. J Exp Med (1992) 176(6):1733–8. doi: 10.1084/jem.176.6.1733 PubMed DOI PMC

Kasparek P, Krausova M, Haneckova R, Kriz V, Zbodakova O, Korinek V, et al. . Efficient gene targeting of the Rosa26 locus in mouse zygotes using tale nucleases. FEBS Lett (2014) 588(21):3982–8. doi: 10.1016/j.febslet.2014.09.014 PubMed DOI

Lo WL, Shah NH, Ahsan N, Horkova V, Stepanek O, Salomon AR, et al. . Lck promotes Zap70-dependent lat phosphorylation by bridging Zap70 to LAT. Nat Immunol (2018) 19(7):733–41. doi: 10.1038/s41590-018-0131-1 PubMed DOI PMC

Ruedl C, Khameneh HJ, Karjalainen K. Manipulation of immune system Via immortal bone marrow stem cells. Int Immunol (2008) 20(9):1211–8. doi: 10.1093/intimm/dxn079 PubMed DOI

Daniels MA, Jameson SC. Critical role for Cd8 in T cell receptor binding and activation by Peptide/Major or histocompatibility complex multimers. J Exp Med (2000) 191(2):335–45. doi: 10.1084/jem.191.2.335 PubMed DOI PMC

Howe KL, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Amode MR, et al. . Ensembl 2021. Nucleic Acids Res (2021) 49(D1):D884–d91. doi: 10.1093/nar/gkaa942 PubMed DOI PMC

Zheng GX, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, et al. . Massively parallel digital transcriptional profiling of single cells. Nat Commun (2017) 8:14049. doi: 10.1038/ncomms14049 PubMed DOI PMC

Lefranc MP, Pommie C, Kaas Q, Duprat E, Bosc N, Guiraudou D, et al. . Imgt unique numbering for immunoglobulin and T cell receptor constant domains and ig superfamily c-like domains. Dev Comp Immunol (2005) 29(3):185–203. doi: 10.1016/j.dci.2004.07.003 PubMed DOI

Bolotin DA, Poslavsky S, Mitrophanov I, Shugay M, Mamedov IZ, Putintseva EV, et al. . Mixcr: Software for comprehensive adaptive immunity profiling. Nat Methods (2015) 12(5):380–1. doi: 10.1038/nmeth.3364 PubMed DOI

Hao Y, Hao S, Andersen-Nissen E, Mauck WM, 3rd, Zheng S, Butler A, et al. . Integrated analysis of multimodal single-cell data. Cell (2021) 184(13):3573–87.e29. doi: 10.1016/j.cell.2021.04.048 PubMed DOI PMC

Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. . Gene ontology: Tool for the unification of biology. the gene ontology consortium. Nat Genet (2000) 25(1):25–9. doi: 10.1038/75556 PubMed DOI PMC

Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event