Mechanisms of Direct and Indirect Presentation of Self-Antigens in the Thymus
Jazyk angličtina Země Švýcarsko Médium electronic-ecollection
Typ dokumentu časopisecké články, přehledy, práce podpořená grantem
PubMed
35774801
PubMed Central
PMC9237256
DOI
10.3389/fimmu.2022.926625
Knihovny.cz E-zdroje
- Klíčová slova
- antigen presentation, central tolerance, cooperative antigen transfer, dendritic cells, thymic epithelial cells, thymus,
- MeSH
- autoantigeny * MeSH
- centrální tolerance MeSH
- dendritické buňky * MeSH
- epitelové buňky MeSH
- receptory antigenů T-buněk MeSH
- thymus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- autoantigeny * MeSH
- receptory antigenů T-buněk MeSH
The inevitability of evolution of the adaptive immune system with its mechanism of randomly rearranging segments of the T cell receptor (TCR) gene is the generation of self-reactive clones. For the sake of prevention of autoimmunity, these clones must be eliminated from the pool of circulating T cells. This process occurs largely in the thymic medulla where the strength of affinity between TCR and self-peptide MHC complexes is the factor determining thymocyte fate. Thus, the display of self-antigens in the thymus by thymic antigen presenting cells, which are comprised of medullary thymic epithelial (mTECs) and dendritic cells (DCs), is fundamental for the establishment of T cell central tolerance. Whereas mTECs produce and present antigens in a direct, self-autonomous manner, thymic DCs can acquire these mTEC-derived antigens by cooperative antigen transfer (CAT), and thus present them indirectly. While the basic characteristics for both direct and indirect presentation of self-antigens are currently known, recent reports that describe the heterogeneity of mTEC and DC subsets, their presentation capacity, and the potentially non-redundant roles in T cell selection processes represents another level of complexity which we are attempting to unravel. In this review, we underscore the seminal studies relevant to these topics with an emphasis on new observations pertinent to the mechanism of CAT and its cellular trajectories underpinning the preferential distribution of thymic epithelial cell-derived self-antigens to specific subsets of DC. Identification of molecular determinants which control CAT would significantly advance our understanding of how the cellularly targeted presentation of thymic self-antigens is functionally coupled to the T cell selection process.
Zobrazit více v PubMed
Langman RE, Cohn M. Editorial Introduction. Semin Immunol (2000) 12:159–62. doi: 10.1006/smim.2000.0227 PubMed DOI
Liu Y-J. A Unified Theory of Central Tolerance in the Thymus. Trends Immunol (2006) 67:215–21. doi: 10.1016/j.it.2006.03.004 PubMed DOI
Sakaguchi S, Powrie F. Emerging Challenges in Regulatory T Cell Function and Biology. Science (2007) 317:627–9. doi: 10.1126/SCIENCE.1142331 PubMed DOI
Hsieh C-S, Lee H-M, Lio C-WJ. Selection of Regulatory T Cells in the Thymus. Nat Rev Immunol (2012) 12:157–67. doi: 10.1038/nri3155 PubMed DOI
Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen Presentation in the Thymus for Positive Selection and Central Tolerance Induction. Nat Rev Immunol (2009) 9:833–44. doi: 10.1038/nri2669 PubMed DOI
Klein L, Kyewski B, Allen PM, Hogquist K. Positive and Negative Selection of the T Cell Repertoire: What Thymocytes See (and Don’t See). Nat Rev Immunol (2014) 14:377–91. doi: 10.1038/nri3667 PubMed DOI PMC
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. . Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein. Science (2002) 298:1395–401. doi: 10.1126/science.1075958 PubMed DOI
Perry JSA, Lio CWJ, Kau AL, Nutsch K, Yang Z, Gordon JI, et al. . Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus. Immunity (2014) 41:414–26. doi: 10.1016/j.immuni.2014.08.007 PubMed DOI PMC
Leventhal DS, Gilmore DC, Berger JM, Nishi S, Lee V, Malchow S, et al. . Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells. Immunity (2016) 44:847–59. doi: 10.1016/j.immuni.2016.01.025 PubMed DOI PMC
Sarkar G, Sommer SS. Access to a Messenger RNA Sequence or its Protein Product is Not Limited by Tissue or Species Specificity. Science (1989) 244:331–4. doi: 10.1126/SCIENCE.2565599 PubMed DOI
Chelly J, Concordet JP, Kaplan JC, Kahn A. Illegitimate Transcription: Transcription of Any Gene in Any Cell Type. Proc Natl Acad Sci U S A (1989) 86:2617–21. doi: 10.1073/PNAS.86.8.2617 PubMed DOI PMC
Linsk R, Gottesman M, Pernis B, Sommer S, Sarkar G. Are Tissues a Patch Quilt of Ectopic Gene Expression? Science (1989) 246:261. doi: 10.1126/science.2799388 PubMed DOI
Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous Gene Expression in Medullary Thymic Epithelial Cells Mirrors the Peripheral Self. Nat Immunol (2001) 2:1032–9. doi: 10.1038/ni723 PubMed DOI
Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, et al. . Tolerance is Established in Polyclonal CD4+ T Cells by Distinct Mechanisms, According to Self-Peptide Expression Patterns. Nat Immunol (2016) 17:187–95. doi: 10.1038/ni.3327 PubMed DOI PMC
Detanico T, Heiser RA, Aviszus K, Bonorino C, Wysocki LJ. Self-Tolerance Checkpoints in CD4 T Cells Specific for a Peptide Derived From the B Cell Antigen Receptor. J Immunol (2011) 187:82–91. doi: 10.4049/jimmunol.1002287 PubMed DOI PMC
Derbinski J, Pinto S, Rösch S, Hexel K, Kyewski B. Promiscuous Gene Expression Patterns in Single Medullary Thymic Epithelial Cells Argue for a Stochastic Mechanism. Proc Natl Acad Sci U S A (2008) 105:657–62. doi: 10.1073/pnas.0707486105 PubMed DOI PMC
Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Kuchler R, et al. . Single-Cell Transcriptome Analysis Reveals Coordinated Ectopic Gene-Expression Patterns in Medullary Thymic Epithelial Cells. Nat Immunol (2015) 16:933–41. doi: 10.1038/ni.3246\r PubMed DOI PMC
Villaseñor J, Besse W, Benoist C, Mathis D. Ectopic Expression of Peripheral-Tissue Antigens in the Thymic Epithelium: Probabilistic, Monoallelic, Misinitiated. Proc Natl Acad Sci U S A (2008) 105:15854–9. doi: 10.1073/pnas.0808069105 PubMed DOI PMC
Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. . Aire-Dependent Thymic Development of Tumor Associated Regulatory T Cells. Science (2013) 339:1219–24. doi: 10.1126/science.1233913 PubMed DOI PMC
Danan-Gotthold M, Guyon C, Giraud M, Levanon EY, Abramson J. Extensive RNA Editing and Splicing Increase Immune Self-Representation Diversity in Medullary Thymic Epithelial Cells. Genome Biol (2016) 17:1–13. doi: 10.1186/s13059-016-1079-9 PubMed DOI PMC
Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, et al. . Population and Single-Cell Genomics Reveal the Aire Dependency, Relief From Polycomb Silencing, and Distribution of Self-Antigen Expression in Thymic Epithelia. Genome Res (2014) 24:1918–31. doi: 10.1101/gr.171645.113 PubMed DOI PMC
Abramson J, Anderson G. Thymic Epithelial Cells. Annurev Immunol (2017) 35:85–118. doi: 10.1146/annurev-immunol PubMed DOI
Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, et al. . Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance. Cell (2015) 163:975–87. doi: 10.1016/j.cell.2015.10.013 PubMed DOI
Meredith M, Zemmour D, Mathis D, Benoist C. Aire Controls Gene Expression in the Thymic Epithelium With Ordered Stochasticity. Nat Immunol (2015) 16:942–9. doi: 10.1038/ni.3247 PubMed DOI PMC
Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire Regulates Negative Selection of Organ-Specific T Cells. Nat Immunol (2003) 4:350–4. doi: 10.1038/ni906 PubMed DOI
Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. The Cellular Mechanism of Aire Control of T Cell Tolerance. Immunity (2005) 23:227–39. doi: 10.1016/j.immuni.2005.07.005 PubMed DOI
Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. . Selection of Foxp3+ Regulatory T Cells Specific for Self Antigen Expressed and Presented by Aire+ Medullary Thymic Epithelial Cells. Nat Immunol (2007) 8:351–8. doi: 10.1038/ni1444 PubMed DOI
Lin J, Yang L, Silva HM, Trzeciak A, Choi Y, Schwab SR, et al. . Increased Generation of Foxp3+regulatory T Cells by Manipulating Antigen Presentation in the Thymus. Nat Commun (2016) 7:1–12. doi: 10.1038/ncomms10562 PubMed DOI PMC
Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells Into the Regulatory T Cell Lineage. Immunity (2016) 44:1102–13. doi: 10.1016/j.immuni.2016.02.009 PubMed DOI PMC
Guerau-de-Arellano M, Martinic M, Benoist C, Mathis D. Neonatal Tolerance Revisited: A Perinatal Window for Aire Control of Autoimmunity. J Exp Med (2009) 206:1245–52. doi: 10.1084/jem.20090300 PubMed DOI PMC
Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D. Regulatory T Cells Generated Early in Life Play a Distinct Role in Maintaining Self-Tolerance. Science (2015) 348:589–94. doi: 10.1126/science.aaa7017 PubMed DOI PMC
Stadinski BD, Blevins SJ, Spidale NA, Duke BR, Huseby PG, Stern LJ, et al. . A Temporal Thymic Selection Switch and Ligand Binding Kinetics Constrain Neonatal Foxp3+ Treg Cell Development. Nat Immunol (2019) 20:1046–58. doi: 10.1038/s41590-019-0414-1 PubMed DOI PMC
Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A, Jenkins MK, et al. . Detection of an Autoreactive T-Cell Population Within the Polyclonal Repertoire That Undergoes Distinct Autoimmune Regulator (Aire)-Mediated Selection. Proc Natl Acad Sci U S A (2012) 109:7847–52. doi: 10.1073/pnas.1120607109 PubMed DOI PMC
Legoux FP, Lim JB, Cauley AW, Dikiy S, Ertelt J, Mariani TJ, et al. . CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion. Immunity (2015) 43:896–908. doi: 10.1016/j.immuni.2015.10.011 PubMed DOI PMC
Hassler T, Urmann E, Teschner S, Federle C, Dileepan T, Schober K, et al. . Inventories of Naive and Tolerant Mouse CD4 T Cell Repertoires Reveal a Hierarchy of Deleted and Diverted T Cell Receptors. Proc Natl Acad Sci U S A (2019) 116:18537–43. doi: 10.1073/pnas.1907615116 PubMed DOI PMC
Bornstein C, Nevo S, Giladi A, Kadouri N, Pouzolles M, Gerbe F, et al. . Single-Cell Mapping of the Thymic Stroma Identifies IL-25-Producing Tuft Epithelial Cells. Nature (2018) 559:622–6. doi: 10.1038/s41586-018-0346-1 PubMed DOI
Miller CN, Proekt I, Von MJ, KL W, AR R, Wang H, et al. . Thymic Tuft Cells Promote an IL-4-Enriched Medulla and Shape Thymocyte Development. Nature (2018) 559:627–31. doi: 10.1038/s41586-018-0345-2 PubMed DOI PMC
Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, Deadman ME, et al. . Ageing Compromises Mouse Thymus Function and Remodels Epithelial Cell Differentiation. Elife (2020) 9:e56221. doi: 10.1101/2020.03.02.973008 PubMed DOI PMC
Park JE, Botting RA, Conde CD, Popescu DM, Lavaert M, Kunz DJ, et al. . A Cell Atlas of Human Thymic Development Defines T Cell Repertoire Formation. Science (2020) 367:1–11. doi: 10.1126/science.aay3224 PubMed DOI PMC
Bautista JL, Cramer NT, Miller CN, Chavez J, Berrios DI, Byrnes LE, et al. . Single-Cell Transcriptional Profiling of Human Thymic Stroma Uncovers Novel Cellular Heterogeneity in the Thymic Medulla. Nat Commun (2021) 12:1–15. doi: 10.1038/s41467-021-21346-6 PubMed DOI PMC
Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, et al. . Promiscuous Gene Expression in Thymic Epithelial Cells is Regulated at Multiple Levels. J Exp Med (2005) 202:33–45. doi: 10.1084/jem.20050471 PubMed DOI PMC
Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y, Kiyonari H, et al. . Aire Controls the Differentiation Program of Thymic Epithelial Cells in the Medulla for the Establishment of Self-Tolerance. J Exp Med (2008) 205:2827–38. doi: 10.1084/jem.20080046 PubMed DOI PMC
Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, Krawisz AK, et al. . Lineage Tracing and Cell Ablation Identify a Post-Aire-Expressing Thymic Epithelial Cell Population. Cell Rep (2013) 5:166–79. doi: 10.1016/j.celrep.2013.08.038 PubMed DOI PMC
Wells KL, Miller CN, Gschwind AR, Wei W, Phipps JD, Anderson MS, et al. . Combined Transient Ablation and Single Cell Rna Sequencing Reveals the Development of Medullary Thymic Epithelial Cells. Elife (2020) 9:1–80. doi: 10.7554/eLife.60188 PubMed DOI PMC
Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y. Lymphotoxin Beta Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells. J Immunol (2013) 190:5110–7. doi: 10.4049/jimmunol.1203203 PubMed DOI
Lucas B, White AJ, Cosway EJ, Parnell SM, James KD, Jones ND, et al. . Diversity in Medullary Thymic Epithelial Cells Controls the Activity and Availability of iNKT Cells. Nat Commun (2020) 11:1–14. doi: 10.1038/s41467-020-16041-x PubMed DOI PMC
Wang J, Sekai M, Matsui T, Fujii Y, Matsumoto M, Takeuchi O, et al. . Hassall ‘ s Corpuscles With Cellular-Senescence Features Maintain IFN α Production Through Neutrophils and pDC Activation in the Thymus. Int Immunol (2019) 31:127–39. doi: 10.1093/intimm/dxy073 PubMed DOI PMC
Hinterberger M, Aichinger M, da Costa OP, Voehringer D, Hoffmann R, Klein L, et al. . Autonomous Role of Medullary Thymic Epithelial Cells in Central CD4(+) T Cell Tolerance. Nat Immunol (2010) 11:512–9. doi: 10.1038/ni.1874 PubMed DOI
Li J, Park J, Foss D, Goldschneider I. Thymus-Homing Peripheral Dendritic Cells Constitute Two of the Three Major Subsets of Dendritic Cells in the Steady-State Thymus. J Exp Med (2009) 206:607–22. doi: 10.1084/jem.20082232 PubMed DOI PMC
Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, et al. . Batf3 Deficiency Reveals a Critical Role for CD8a+ Dendritic Cells in Cytotoxic T Cell Immunity. Science (2008) 322:1097–101. doi: 10.1126/science.1164206 PubMed DOI PMC
Guilliams M, Dutertre C, Scott CL, McGovern N, Sichiene D, Chakarov S, et al. . Unsupervised High-Dimensional Analysis Aligns Dendritic Cells Across Tissues and Species. Immunity (2016) 45:669–84. doi: 10.1016/j.immuni.2016.08.015 PubMed DOI PMC
Ohnmacht C, Pullner A, King SBS, Drexler I, Meier S, Brocker T, et al. . Constitutive Ablation of Dendritic Cells Breaks Self-Tolerance of CD4 T Cells and Results in Spontaneous Fatal Autoimmunity. J Exp Med (2009) 206:549–59. doi: 10.1084/jem.20082394 PubMed DOI PMC
Vobořil M, Brabec T, Dobeš J, Šplíchalová I, Březina J, Čepková A, et al. . Toll-Like Receptor Signaling in Thymic Epithelium Controls Monocyte-Derived Dendritic Cell Recruitment and Treg Generation. Nat Commun (2020) 11:1–16. doi: 10.1038/s41467-020-16081-3 PubMed DOI PMC
Ardouin L, Luche H, Chelbi R, Carpentier S, Shawket A, Sanchis FM, et al. . Broad and Largely Concordant Molecular Changes Characterize Tolerogenic and Immunogenic Dendritic Cell Maturation in Thymus and Periphery. Immunity (2016) 45:305–18. doi: 10.1016/j.immuni.2016.07.019 PubMed DOI
Oh J, Wu N, Barczak AJ, Barbeau R, Erle DJ, Shin J-S. CD40 Mediates Maturation of Thymic Dendritic Cells Driven by Self-Reactive CD4 + Thymocytes and Supports Development of Natural Regulatory T Cells. J Immunol (2018) 200:1399–412. doi: 10.4049/jimmunol.1700768 PubMed DOI PMC
Van Kaer L, Wu L, Joyce S. Mechanisms and Consequences of Antigen Presentation by CD1. Trends Immunol (2016) 37:738–54. doi: 10.1016/j.it.2016.08.011 PubMed DOI PMC
Baba T, Nakamoto Y, Mukaida N. Crucial Contribution of Thymic Sirp + Conventional Dendritic Cells to Central Tolerance Against Blood-Borne Antigens in a CCR2-Dependent Manner. J Immunol (2009) 183:3053–63. doi: 10.4049/jimmunol.0900438 PubMed DOI
Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. Clonal Deletion of Thymocytes by Circulating Dendritic Cells Homing to the Thymus. Nat Immunol (2006) 7:1092–100. doi: 10.1038/ni1385 PubMed DOI
Vollmann EH, Rattay K, Barreiro O, Thiriot A, Fuhlbrigge RA, Vrbanac V, et al. . Specialized Transendothelial Dendritic Cells Mediate Thymic T-Cell Selection Against Blood-Borne Macromolecules. Nat Commun (2021) 12:1–19. doi: 10.1038/s41467-021-26446-x PubMed DOI PMC
Zegarra-Ruiz DF, Kim DV, Norwood K, Kim M, Wu WJH, Saldana-Morales FB, et al. . Thymic Development of Gut-Microbiota-Specific T Cells. Nature (2021) 594:413–7. doi: 10.1038/s41586-021-03531-1 PubMed DOI PMC
Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, et al. . Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance. Immunity (2012) 36:438–50. doi: 10.1016/j.immuni.2012.01.017 PubMed DOI PMC
Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S, Pinto S, et al. . Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction. Immunity (2015) 42:1048–61. doi: 10.1016/j.immuni.2015.05.013 PubMed DOI
Perera J, Zheng Z, Li S, Gudjonson H, Kalinina O, Benichou JIC, et al. . Self-Antigen-Driven Thymic B Cell Class Switching Promotes T Cell Central Tolerance. Cell Rep (2016) 17:387–98. doi: 10.1016/j.celrep.2016.09.011 PubMed DOI PMC
Perera J, Meng L, Meng F, Huang H. Autoreactive Thymic B Cells are Efficient Antigen-Presenting Cells of Cognate Self-Antigens for T Cell Negative Selection. Proc Natl Acad Sci U S A (2013) 110:17011–6. doi: 10.1073/pnas.1313001110 PubMed DOI PMC
Munthe LA, Corthay A, Os A, Zangani M, Bogen B. Systemic Autoimmune Disease Caused by Autoreactive B Cells That Receive Chronic Help From Ig V Region-Specific T Cells. J Immunol (2005) 175:2391–400. doi: 10.4049/jimmunol.175.4.2391 PubMed DOI
Greaves RB, Chen D, Green EA. Thymic B Cells as a New Player in the Type 1 Diabetes Response. Front Immunol (2021) 12:772017/BIBTEX. doi: 10.3389/FIMMU.2021.772017/BIBTEX PubMed DOI PMC
Klein L. Dead Man Walking: How Thymocytes Scan the Medulla. Nat Immunol (2009) 10:809–11. doi: 10.1038/ni0809-809 PubMed DOI
Sakata M, Ohigashi I, Takahama Y. Cellularity of Thymic Epithelial Cells in the Postnatal Mouse. J Immunol (2018) 200:1382–8. doi: 10.4049/jimmunol.1701235 PubMed DOI
Perry JSA, Hsieh CS. Development of T-Cell Tolerance Utilizes Both Cell-Autonomous and Cooperative Presentation of Self-Antigen. Immunol Rev (2016) 271:141–55. doi: 10.1111/imr.12403 PubMed DOI PMC
Gallegos AM, Bevan MJ. Central Tolerance to Tissue-Specific Antigens Mediated by Direct and Indirect Antigen Presentation. J Exp Med (2004) 200:1039–49. doi: 10.1084/jem.20041457 PubMed DOI PMC
Mccaughtry TM, Wilken MS, Hogquist KA. Thymic Emigration Revisited. J Exp Med (2007) 204:2513–20. doi: 10.1084/jem.20070601 PubMed DOI PMC
Mouri Y, Ueda Y, Yamano T, Matsumoto M, Tsuneyama K, Kinashi T, et al. . Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self-Antigen and Those That Present Antigen. J Immunol (2017) 199:3959–71. doi: 10.4049/jimmunol.1700892 PubMed DOI
Hubert F-X, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, et al. . Aire Regulates the Transfer of Antigen From mTECs to Dendritic Cells for Induction of Thymic Tolerance. Blood (2011) 118:2462–72. doi: 10.1182/blood-2010-06-286393.An PubMed DOI
Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, Jeker LT, et al. . Aire-Dependent Production of XCL1 Mediates Medullary Accumulation of Thymic Dendritic Cells and Contributes to Regulatory T Cell Development. J Exp Med (2011) 208:383–94. doi: 10.1084/jem.20102327 PubMed DOI PMC
Morimoto J, Matsumoto M, Miyazawa R, Yoshida H, Tsuneyama K, Matsumoto M. Aire Suppresses CTLA-4 Expression From the Thymic Stroma to Control Autoimmunity. Cell Rep (2022) 38:110384. doi: 10.1016/J.CELREP.2022.110384 PubMed DOI
Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL, Jenkinson EJ, et al. . The Thymic Medulla is Required for Foxp3 + Regulatory But Not Conventional CD4 + Thymocyte Development. J Exp Med (2013) 210:675–81. doi: 10.1084/jem.20122070 PubMed DOI PMC
McCaughtry TM, Baldwin TA, Wilken MS, Hogquist KA. Clonal Deletion of Thymocytes can Occur in the Cortex With No Involvement of the Medulla. J Exp Med (2008) 205:2575–84. doi: 10.1084/jem.20080866 PubMed DOI PMC
Breed ER, Watanabe M, Hogquist KA. Population Level Measuring Thymic Clonal Deletion at the. J Immunol (2019) 202:3226–33. doi: 10.4049/jimmunol.1900191 PubMed DOI PMC
Lancaster JN, Thyagarajan HM, Srinivasan J, Li Y, Hu Z, Ehrlich LIR. Live-Cell Imaging Reveals the Relative Contributions of Antigen-Presenting Cell Subsets to Thymic Central Tolerance. Nat Commun (2019) 10. doi: 10.1038/s41467-019-09727-4 PubMed DOI PMC
Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, et al. . Differential Antigen Processing by Dendritic Cell Subsets in Vivo. Science (2007) 315:107–12. doi: 10.1126/science.1136080 PubMed DOI
Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. Autophagy in Thymic Epithelium Shapes the T-Cell Repertoire and is Essential for Tolerance. Nature (2008) 455:396–400. doi: 10.1038/nature07208 PubMed DOI
Aichinger M, Wu C, Nedjic J, Klein L. Macroautophagy Substrates are Loaded Onto MHC Class II of Medullary Thymic Epithelial Cells for Central Tolerance. J Exp Med (2013) 210:287–300. doi: 10.1084/jem.20122149 PubMed DOI PMC
Koble C, Kyewski B. The Thymic Medulla: A Unique Microenvironment for Intercellular Self-Antigen Transfer. J Exp Med (2009) 206:1505–13. doi: 10.1084/jem.20082449 PubMed DOI PMC
Guerri L, Peguillet I, Geraldo Y, Nabti S, Premel V, Lantz O. Analysis of APC Types Involved in CD4 Tolerance and Regulatory T Cell Generation Using Reaggregated Thymic Organ Cultures. J Immunol (2013) 190:2102–10. doi: 10.4049/jimmunol.1202883 PubMed DOI
Liu YJ, Román E, Shino H, Qin X-F. Cutting Edge: Hematopoietic-Derived APCs Select Regulatory T Cells in Thymus. J Immunol (2010) 185:3819–23. doi: 10.4049/jimmunol.0900665 PubMed DOI PMC
Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D’Amico A, Steptoe RJ, et al. . Dendritic Cells in the Thymus Contribute to T-Regulatory Cell Induction. Proc Natl Acad Sci (2008) 105:19869–74. doi: 10.1073/pnas.0810268105 PubMed DOI PMC
Vobořil M, Březina J, Brabec T, Dobeš J, Ballek O, Dobešová M, et al. . A Model of Preferential Pairing Between Epithelial and Dendritic Cells in Thymic Antigen Transfer. Elife (2022) 11:e71578. doi: 10.7554/ELIFE.71578 PubMed DOI PMC
Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper ML, Choi J, et al. . Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allotolerance. Immunity (2018) 48:923–36.e4. doi: 10.1016/j.immuni.2018.04.007 PubMed DOI PMC
Herbin O, Bonito AJ, Jeong S, Weinstein EG, Rahman AH, Xiong H, et al. . Medullary Thymic Epithelial Cells and CD8α+Dendritic Cells Coordinately Regulate Central Tolerance But CD8α+Cells are Dispensable for Thymic Regulatory T Cell Production. J Autoimmun (2016) 75:141–9. doi: 10.1016/j.jaut.2016.08.002 PubMed DOI PMC
MacNabb BW, Kline DE, Albright AR, Chen X, Leventhal DS, Savage PA, et al. . Negligible Role for Deletion Mediated by Cdc1 in CD8+ T Cell Tolerance. J Immunol (2019) 202:2628–35. doi: 10.4049/jimmunol.1801621 PubMed DOI PMC
Joffre OP, Segura E, Savina A, Amigorena S. Cross-Presentation by Dendritic Cells. Nat Rev Immunol (2012) 12:557–69. doi: 10.1038/nri3254 PubMed DOI
Hu Z, Li Y, Van Nieuwenhuijze A, Selden HJ, Jarrett AM, Sorace AG, et al. . CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment. Cell Rep (2017) 21:168–80. doi: 10.1016/j.celrep.2017.09.016 PubMed DOI PMC
Kurd NS, Lutes LK, Yoon J, Chan SW, Dzhagalov IL, Hoover AR, et al. . A Role for Phagocytosis in Inducing Cell Death During Thymocyte Negative Selection. Elife (2020) 9:1–18. doi: 10.7554/eLife.56027 PubMed DOI PMC
Humblet C, Rudensky AY, Kyewski B. Presentation and Intercellular Transfer of Self Antigen Within the Thymic Microenvironment: Expression of the Eα Peptide-L-Abcomplex by Isolated Thymic Stromal Cells. Int Immunol (1994) 6:1949–58. doi: 10.1093/intimm/6.12.1949 PubMed DOI
Kroger CJ, Spidale NA, Wang B, Tisch R. Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer. J Immunol (2017) 198:249–56. doi: 10.4049/jimmunol.1601516 PubMed DOI PMC
Skogberg G, Lundberg V, Berglund M, Gudmundsdottir J, Telemo E, Lindgren S, et al. . Human Thymic Epithelial Primary Cells Produce Exosomes Carrying Tissue-Restricted Antigens. Immunol Cell Biol (2015) 93:727–34. doi: 10.1038/icb.2015.33 PubMed DOI PMC
Millet V, Naquet P, Guinamard RR. Intercellular MHC Transfer Between Thymic Epithelial and Dendritic Cells. Eur J Immunol (2008) 38:1257–63. doi: 10.1002/eji.200737982 PubMed DOI
Dopfer EP, Minguet S, Schamel WWA. A New Vampire Saga: The Molecular Mechanism of T Cell Trogocytosis. Immun (2011) 35:151–3. doi: 10.1016/j.immuni.2011.08.004 PubMed DOI
Miyake K, Shiozawa N, Nagao T, Yoshikawa S, Yamanishi Y, Karasuyama H. Trogocytosis of Peptide-MHC Class II Complexes From Dendritic Cells Confers Antigen-Presenting Ability on Basophils. Proc Natl Acad Sci U S A (2017) 114:1111–6. doi: 10.1073/PNAS.1615973114 PubMed DOI PMC
Neijssen J, Herberts C, Drijfhout JW, Reits E, Janssen L, Neefjes J. Cross-Presentation by Intercellular Peptide Transfer Through Gap Junctions. Nature (2005) 434:83–8. doi: 10.1038/NATURE03290 PubMed DOI
Gray D, Abramson J, Benoist C, Mathis D. Proliferative Arrest and Rapid Turnover of Thymic Epithelial Cells Expressing Aire. J Exp Med (2007) 204:2521–8. doi: 10.1084/jem.20070795 PubMed DOI PMC
Maier B, Leader AM, Chen ST, Tung N, Chang C, LeBerichel J, et al. . A Conserved Dendritic-Cell Regulatory Program Limits Antitumour Immunity. Nature (2020) 580:257–62. doi: 10.1038/s41586-020-2134-y PubMed DOI PMC
Abramson J, Giraud M, Benoist C, Mathis D. Aire’s Partners in the Molecular Control of Immunological Tolerance. Cell (2010) 140:123–35. doi: 10.1016/j.cell.2009.12.030 PubMed DOI
Guha M, Saare M, Maslovskaja J, Kisand K, Liiv I, Haljasorg U, et al. . DNA Breaks and Chromatin Structural Changes Enhance the Transcription of Autoimmune Regulator Target Genes. J Biol Chem (2017) 292:6542–54. doi: 10.1074/jbc.M116.764704 PubMed DOI PMC
Lopes N, Charaix J, Cédile O, Sergé A, Irla M. Lymphotoxin α Fine-Tunes T Cell Clonal Deletion by Regulating Thymic Entry of Antigen-Presenting Cells. Nat Commun (2018) 9:1–16. doi: 10.1016/j.bbrc.2013.06.084 PubMed DOI PMC
Kadouri N, Nevo S, Goldfarb Y, Abramson J. Thymic Epithelial Cell Heterogeneity: TEC by TEC. Nat Rev Immunol (2020) 20:239–53. doi: 10.1038/s41577-019-0238-0 PubMed DOI
Watanabe N, Wang Y, Lee HK, Ito T, Wang Y, Cao W, et al. . Hassall ‘ s Corpuscles Instruct Dendritic Cells to Induce CD4+ CD25+ Regulatory T Cells in Human Thymus. Nature (2005) 436:1181–5. doi: 10.1038/nature03886 PubMed DOI
Gordon J, Xiao S, Iii BH, Su D, Navarre SP, Condie BG, et al. . Specific Expression of lacZ and Cre Recombinase in Fetal Thymic Epithelial Cells by Multiplex Gene Targeting at the Foxn1 Locus. BMC Dev Biol Biol (2007) 7:1–12. doi: 10.1186/1471-213X-7-69 PubMed DOI PMC
Tykocinski LO, Sinemus A, Rezavandy E, Weiland Y, Baddeley D, Cremer C, et al. . Epigenetic Regulation of Promiscuous Gene Expression in Thymic Medullary Epithelial Cells. Proc Natl Acad Sci U S A (2010) 107:19426–31. doi: 10.1073/pnas.1009265107 PubMed DOI PMC
Dobeš J, Neuwirth A, Dobešová M, Vobořil M, Balounová J, Ballek O, et al. . Gastrointestinal Autoimmunity Associated With Loss of Central Tolerance to Enteric α-Defensins. Gastroenterology (2015) 149:139–50. doi: 10.1053/j.gastro.2015.05.009 PubMed DOI
Breed ER, Lee ST, Hogquist KA. Directing T Cell Fate: How Thymic Antigen Presenting Cells Coordinate Thymocyte Selection. Semin Cell Dev Biol (2018) 84:2–10. doi: 10.1016/j.semcdb.2017.07.045 PubMed DOI PMC