Antigen transfer in the thymus

Antigen transfer in the thymus is the transmission of self-antigens between thymic Antigen presenting cells (APCs) which contributes to the establishment of T cell central tolerance.[1]

Thymus represents an origin of T cell development and its responsibility is to select functional but also safe T cells which will not attack self tissues. Self-harmful T cells, further referred to as autoreactive T cells, originate in the thymus because of the stochastic process called V(D)J recombination which conducts the generation of T cell receptors (TCRs) and enables their limitless variability. Two processes of central tolerance take place in thymic medulla, namely clonal deletion (recessive tolerance) and T Regulatory cells selection (dominant tolerance) which force autoreactive T cells to apoptosis or skew them into suppressor T regulatory cells (TRegs), respectively, in order to protect body against manifestations of autoimmunity.

These processes are mediated especially by unique subset of stromal cells called Medullary thymic epithelial cells (mTECs) via presentation of Tissue restricted antigens (TRAs) that represent self tissues from almost all parts of the body.[2]

mTECs

mTECs are not only capable to present TRAs as efficient APCs. They are also potent in production of these TRAs via unique process called promiscuous gene expression (PGE)[3] and might serve as their reservoir.

Drawbacks of antigen presentation

mTECs as APCs reveal some drawbacks on population level. Their numbers in thymic medulla reach only 100,000 per 2-week-old thymus.[4] Furthermore, average lifespan of mTECs does not exceed 2–3 days,[5] probably due to only known PGE activator Autoimmune regulator (Aire),[6] which requires for its proper function generation of DNA double strand breaks.[7] And last but not least, each TRA is expressed only by 1-3% of mTEC population.[8] These facts decrease the chance of efficient recessive or dominant tolerance.

Relevance of antigen transfer

Unidirectional spreading of mTEC-derived TRAs onto additional APCs via antigen transfer increases the probability of encounter between potential autoreactive T cell and its corresponding TRA and therefore enhances processes of central tolerance. Furthermore, antigen transfer enables TRA processing and presentation by different cellular microenvironments.

Despite relevance of antigen transfer, seminal study was published, showing mTECs to form fully established central tolerance without support of additional APCs.[9]

Antigen transfer enables indirect presentation of TRAs

First article which touches antigen transfer was published in 2004. Experiments from this study reveal that clonal deletion of autoreactive CD4+ T cells, apart from CD8+ T cells, requires indirect presentation of TRAs by bone marrow (BM) derived APCs. Direct presentation of TRAs by mTECs was shown to be insufficient in this case.[10] Requirement of indirect presentation of some mTEC-derived TRAs in the case of recessive tolerance was perceived also by additional studies which both firstly demonstrated antigen transfer as an instrument that enables this process.[11][12] Need of TRA indirect presentation is probably closely related with above mentioned "processing of TRAs by different microenvironments".

N.B.: BM derived APCs don´t express TRAs, this process is uniquely dedicated to mTECs. Exception is represented by thymic B cells which were shown to express TRAs and Aire.[13][14]

Thymic dendritic cells

Systemic ablation of dendritic cells (DCs) was shown to cause fatal manifestations of autoimmunity[15] which points to their importance in central tolerance. Indeed, as mTECs represent exclusive donors of TRAs, experiments with first antigen transfer mouse models discovered thymic dendritic cells (DCs) to be so far the only known TRAs acceptors involved in antigen transfer.[11][12] Indispensability of DCs for the establishment of central tolerance was further verified by recent analysis, which revealed that DCs mediate both recessive and dominant tolerance, with preference for the latter, via presentation of more common TRAs.[16][17]

Subsets

tDCs

The most efficient subset in TRA presentation and both modes of central tolerance was found to be CD8α+ thymic-derived DCs (tDCs).[16] This subset was also shown to express XCR1 and to be attracted by mTECs via XCL1 chemokine expression.[18] tDCs rise intrathymically and constitute approximately half of thymic DCs population.[19]

mDCs

Sirpα+ migratory DCs (mDCs) form second subset of thymic DCs.[20] They rise extrathymically, and were shown to present self antigens, especially blood-borne antigens, in the thymus, which they acquire in the periphery.[21] They were also shown to be more efficient in T regulatory cells selection than clonal deletion.[19]

pDCs

The last abundant subset of thymic DCs is represented by B220+ plasmacytoid DCs (pDCs)[20] which also rise extrathymically and transfer peripheral antigens from the periphery to the thymus to mediate selection processes.[22]

All these thymic DC subsets were shown to participate in antigen transfer. Nevertheless, only tDCs and mDCs were observed to utilize transferred TRAs for indirect presentation which led to the processes of central tolerance.[23]

Mechanism

The unambiguous mechanism of the antigen transfer is still unknown. However, there are three possible ways: I. acquisition of mTEC apoptotic bodies, which could possibly be related with low mTEC lifespan[5] II. acquisition of exosomes and III. acquisition via trogocytosis, how antigen transfer can be mediated.[11][12][23]

There is also an evidence, that antigen transfer and therefore indirect presentation by thymic DCs are regulated by PGE activator Aire.[24]

References

  1. ↑ Breed, Elise R.; Lee, S. Thera; Hogquist, Kristin A. (2018). "Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection". Seminars in Cell & Developmental Biology. 84: 2–10. doi:10.1016/j.semcdb.2017.07.045. PMC 5807247. PMID 28800929.
  2. ↑ Klein L, Kyewski B, Allen PM, Hogquist KA (June 2014). "Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)". Nature Reviews. Immunology. 14 (6): 377–91. doi:10.1038/nri3667. PMC 4757912. PMID 24830344.
  3. ↑ Derbinski J, Schulte A, Kyewski B, Klein L (November 2001). "Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self". Nature Immunology. 2 (11): 1032–9. doi:10.1038/ni723. PMID 11600886. S2CID 20155713.
  4. ↑ Klein L (August 2009). "Dead man walking: how thymocytes scan the medulla". Nature Immunology. 10 (8): 809–11. doi:10.1038/ni0809-809. PMID 19621041. S2CID 28668641.
  5. 1 2 Gray D, Abramson J, Benoist C, Mathis D (October 2007). "Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire". The Journal of Experimental Medicine. 204 (11): 2521–8. doi:10.1084/jem.20070795. PMC 2118482. PMID 17908938.
  6. ↑ Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (November 2002). "Projection of an immunological self shadow within the thymus by the aire protein". Science. 298 (5597): 1395–401. Bibcode:2002Sci...298.1395A. doi:10.1126/science.1075958. PMID 12376594. S2CID 13989491.
  7. ↑ Guha M, Saare M, Maslovskaja J, Kisand K, Liiv I, Haljasorg U, Tasa T, Metspalu A, Milani L, Peterson P (April 2017). "DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes". The Journal of Biological Chemistry. 292 (16): 6542–6554. doi:10.1074/jbc.m116.764704. PMC 5399106. PMID 28242760.
  8. ↑ Derbinski J, Pinto S, Rösch S, Hexel K, Kyewski B (January 2008). "Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism". Proceedings of the National Academy of Sciences of the United States of America. 105 (2): 657–62. Bibcode:2008PNAS..105..657D. doi:10.1073/pnas.0707486105. PMC 2206592. PMID 18180458.
  9. ↑ Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L (June 2010). "Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance". Nature Immunology. 11 (6): 512–9. doi:10.1038/ni.1874. PMID 20431619. S2CID 33154019.
  10. ↑ Gallegos AM, Bevan MJ (October 2004). "Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation". The Journal of Experimental Medicine. 200 (8): 1039–49. doi:10.1084/jem.20041457. PMC 2211843. PMID 15492126.
  11. 1 2 3 Millet V, Naquet P, Guinamard RR (May 2008). "Intercellular MHC transfer between thymic epithelial and dendritic cells". European Journal of Immunology. 38 (5): 1257–63. doi:10.1002/eji.200737982. PMID 18412162.
  12. 1 2 3 Koble C, Kyewski B (July 2009). "The thymic medulla: a unique microenvironment for intercellular self-antigen transfer". The Journal of Experimental Medicine. 206 (7): 1505–13. doi:10.1084/jem.20082449. PMC 2715082. PMID 19564355.
  13. ↑ Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S, Pinto S, Gerdes N, Lutgens E, Ishimaru N, Busslinger M, Brors B, Kyewski B, Klein L (June 2015). "Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction". Immunity. 42 (6): 1048–61. doi:10.1016/j.immuni.2015.05.013. PMID 26070482.
  14. ↑ Dobeš J, Edenhofer F, Vobořil M, Brabec T, Dobešová M, Čepková A, Klein L, Rajewsky K, Filipp D (November 2017). "A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire". European Journal of Immunology. 48 (3): 546–548. doi:10.1002/eji.201747267. PMID 29193031.
  15. ↑ Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, Voehringer D (March 2009). "Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity". The Journal of Experimental Medicine. 206 (3): 549–59. doi:10.1084/jem.20082394. PMC 2699126. PMID 19237601.
  16. 1 2 Perry JS, Lio CJ, Kau AL, Nutsch K, Yang Z, Gordon JI, Murphy KM, Hsieh CS (September 2014). "Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus". Immunity. 41 (3): 414–426. doi:10.1016/j.immuni.2014.08.007. PMC 4175925. PMID 25220213.
  17. ↑ Leventhal DS, Gilmore DC, Berger JM, Nishi S, Lee V, Malchow S, Kline DE, Kline J, Vander Griend DJ, Huang H, Socci ND, Savage PA (April 2016). "Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells". Immunity. 44 (4): 847–59. doi:10.1016/j.immuni.2016.01.025. PMC 4842258. PMID 27037189.
  18. ↑ Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, Jeker LT, Bösl MR, Holländer GA, Hayashi Y, Malefyt Rde W, Nitta T, Takahama Y (February 2011). "Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development". The Journal of Experimental Medicine. 208 (2): 383–94. doi:10.1084/jem.20102327. PMC 3039864. PMID 21300913.
  19. 1 2 Hadeiba H, Butcher EC (June 2013). "Thymus-homing dendritic cells in central tolerance". European Journal of Immunology. 43 (6): 1425–9. doi:10.1002/eji.201243192. PMC 3774955. PMID 23616226.
  20. 1 2 Li J, Park J, Foss D, Goldschneider I (March 2009). "Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus". The Journal of Experimental Medicine. 206 (3): 607–22. doi:10.1084/jem.20082232. PMC 2699131. PMID 19273629.
  21. ↑ Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH (October 2006). "Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus". Nature Immunology. 7 (10): 1092–100. doi:10.1038/ni1385. PMID 16951687. S2CID 9162653.
  22. ↑ Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, Nguyen L, Ghodsi A, Adler S, Butcher EC (March 2012). "Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance". Immunity. 36 (3): 438–50. doi:10.1016/j.immuni.2012.01.017. PMC 3315699. PMID 22444632.
  23. 1 2 Kroger CJ, Spidale NA, Wang B, Tisch R (January 2017). "Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer". Journal of Immunology. 198 (1): 249–256. doi:10.4049/jimmunol.1601516. PMC 5173434. PMID 27895179.
  24. ↑ Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, Proietto AI, Cannon PZ, Forehan S, Smyth GK, Wu L, Goodnow CC, Carbone FR, Scott HS, Heath WR (September 2011). "Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance". Blood. 118 (9): 2462–72. doi:10.1182/blood-2010-06-286393. PMID 21505196.
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