T cell receptor revision

T-cell receptor revision (alternative term: antigen receptor editing) is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus[1] or better eliminate such self-reactive T cells[2] on the other hand and thus contributing to peripheral tolerance - the extent of each has not been completely understood yet.[3][4][5] This process occurs during follicular helper T cell formation in lymph node germinal centers.[6][7]

T cell revision is achieved via reactivation of recombination enzymes RAG1 and/or RAG2 after T cell activation in the periphery and random recombination of their CDR sequences. Post-revision peripheral T cell repertoire is strengthening all essential features of self-tolerant and self-MHC-restricted T cell repertoire generated in the thymus while keeping all its hallmarks - reactivity towards foreign antigens and homeostatic proliferation in response to self-MHC, so-called tonic signaling.[5]

Background of T cell specificity regulation

The initial diversification processes (somatic V(D)J recombination or gene conversion and nucleotide addition) occur in the primary lymphoid organ (thymus) and lead to very high diversity (> 1014) of TCRs, which are able to recognize almost any antigenic structure/sequence. The paradigm of adaptive immunity is that a single T cell is educated only in thymus and at the exit from thymus it can express only a single TCR with unique and definitive antigen specificity which cannot be modified. It is not correct since dual receptor T cells do exist in the periphery and the single receptor T cells can modify its specificity or regain a second TCR there.[8][9][10] Those T cells recognizing self-structures (peptide/MHC complexes) are eliminated in the thymus immediately in a process of central tolerance, however it is not 100% effective again. As a result, there are many self-reactive T cells emigrating from thymus to the periphery and performing their effector functions there, including cytototoxic and helper activities, finally leading to autoimmunity. Peripheral tolerance is a mechanism controlling such autoreactive T cells in secondary lymphoid organs, blood circulation and all non-lymphoid tissues by different means. TCR revision process is generating much higher T cell plasticity in the development of the adaptive immune system than we have previously anticipated.

Evidence for TCR revision

Activation-dependent T cell revision process is part of peripheral tolerance mechanisms if the new TCR specificity loses its autoreactive specificity as described in mouse transgenic[11] and knock-in[12][13] mouse models or in self-reactive conventional T cells in mouse[13][14] or man.[15] Since this process is random, it might also lead to de novo appearance of autoreactive TCRs on initially non-self reactive T cells or even switch between T cell lineages such as T regulatory cells and Th17 cells[16] or gamma/delta and alpha/beta T cells.[17]

The current knowledge on antigen receptor editing both in T cells and B cells is far from complete, but it has an essential impact on the central dogma of immunology - the control of adaptive immune cells, their specificity and regulation.

References
  1. Vaitaitis, Gisela M.; Poulin, Michelle; Sanderson, Richard J.; Haskins, Kathryn; Wagner, David H. (Apr 1, 2003). "Cutting edge: CD40-induced expression of recombination activating gene (RAG) 1 and RAG2: a mechanism for the generation of autoaggressive T cells in the periphery". Journal of Immunology. 170 (7): 3455–3459. doi:10.4049/jimmunol.170.7.3455. ISSN 0022-1767. PMID 12646605.
  2. Simmons, Kalynn B.; Wubeshet, Maramawit; Ames, Kristina T.; McMahan, Catherine J.; Hale, J. Scott; Fink, Pamela J. (2012). "Modulation of TCRβ surface expression during TCR revision". Cellular Immunology. 272 (2): 124–129. doi:10.1016/j.cellimm.2011.10.022. ISSN 1090-2163. PMC 3244515. PMID 22138498.
  3. Mostoslavsky, Raul; Alt, Frederick W. (Jun 2004). "Receptor revision in T cells: an open question?". Trends in Immunology. 25 (6): 276–279. doi:10.1016/j.it.2004.04.001. ISSN 1471-4906. PMID 15145316.
  4. Wagner, David H. (Apr 2007). "Re-shaping the T cell repertoire: TCR editing and TCR revision for good and for bad". Clinical Immunology (Orlando, Fla.). 123 (1): 1–6. doi:10.1016/j.clim.2006.08.006. ISSN 1521-6616. PMID 16990051.
  5. Hale, J. Scott; Fink, Pamela J. (Apr 2010). "T-cell receptor revision: friend or foe?". Immunology. 129 (4): 467–473. doi:10.1111/j.1365-2567.2010.03250.x. ISSN 1365-2567. PMC 2842493. PMID 20201984.
  6. Cooper, Cristine J.; Turk, Gail L.; Sun, Mingyi; Farr, Andrew G.; Fink, Pamela J. (Dec 1, 2004). "Cutting edge: TCR revision occurs in germinal centers". Journal of Immunology. 173 (11): 6532–6536. doi:10.4049/jimmunol.173.11.6532. ISSN 0022-1767. PMID 15557142.
  7. Higdon, Lauren E.; Deets, Katherine A.; Friesen, Travis J.; Sze, Kai-Yin; Fink, Pamela J. (Apr 15, 2014). "Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions". Proceedings of the National Academy of Sciences of the United States of America. 111 (15): 5652–5657. Bibcode:2014PNAS..111.5652H. doi:10.1073/pnas.1321803111. ISSN 1091-6490. PMC 3992682. PMID 24706795.
  8. He, Xin; Janeway, Charles A.; Levine, Matthew; Robinson, Eve; Preston-Hurlburt, Paula; Viret, Christophe; Bottomly, Kim (Feb 2002). "Dual receptor T cells extend the immune repertoire for foreign antigens". Nature Immunology. 3 (2): 127–134. doi:10.1038/ni751. ISSN 1529-2908. PMID 11812989. S2CID 23163549.
  9. Morris, Gerald P.; Allen, Paul M. (Jun 1, 2009). "Cutting edge: Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease". Journal of Immunology. 182 (11): 6639–6643. doi:10.4049/jimmunol.0900638. ISSN 1550-6606. PMC 3196624. PMID 19454656.
  10. Ni, Peggy P.; Solomon, Benjamin; Hsieh, Chyi-Song; Allen, Paul M.; Morris, Gerald P. (Aug 15, 2014). "The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires". Journal of Immunology. 193 (4): 1778–1786. doi:10.4049/jimmunol.1400532. ISSN 1550-6606. PMC 4119549. PMID 25015825.
  11. McMahan, C. J.; Fink, P. J. (November 1998). "RAG reexpression and DNA recombination at T cell receptor loci in peripheral CD4+ T cells". Immunity. 9 (5): 637–647. doi:10.1016/s1074-7613(00)80661-5. ISSN 1074-7613. PMID 9846485.
  12. Huang, Ching-Yu; Golub, Rachel; Wu, Gillian E.; Kanagawa, Osami (Apr 1, 2002). "Superantigen-induced TCR alpha locus secondary rearrangement: role in tolerance induction". Journal of Immunology. 168 (7): 3259–3265. doi:10.4049/jimmunol.168.7.3259. ISSN 0022-1767. PMID 11907080.
  13. Takase, Mitsuyo; Kanagawa, Edith M.; Kanagawa, Osami (Aug 15, 2007). "Age-dependent TCR revision mediated by interaction between alphabeta TCR and self-antigens". Journal of Immunology. 179 (4): 2163–2169. doi:10.4049/jimmunol.179.4.2163. ISSN 0022-1767. PMID 17675475.
  14. Bynoe, Margaret S.; Viret, Christophe; Flavell, Richard A.; Janeway, Charles A. (Feb 22, 2005). "T cells from epicutaneously immunized mice are prone to T cell receptor revision". Proceedings of the National Academy of Sciences of the United States of America. 102 (8): 2898–2903. Bibcode:2005PNAS..102.2898B. doi:10.1073/pnas.0409880102. ISSN 0027-8424. PMC 549496. PMID 15708975.
  15. Lantelme, Erica; Orlando, Luca; Porcedda, Paola; Turinetto, Valentina; De Marchi, Mario; Amoroso, Antonio; Mantovani, Stefania; Giachino, Claudia (Jan 2008). "An in vitro model of T cell receptor revision in mature human CD8+ T cells". Molecular Immunology. 45 (2): 328–337. doi:10.1016/j.molimm.2007.06.153. ISSN 0161-5890. PMID 17659780.
  16. Zehn, Dietmar; Bevan, Michael J.; Fink, Pamela J. (Nov 1, 2007). "Cutting edge: TCR revision affects predominantly Foxp3 cells and skews them toward the Th17 lineage". Journal of Immunology. 179 (9): 5653–5657. doi:10.4049/jimmunol.179.9.5653. ISSN 0022-1767. PMC 2776039. PMID 17947636.
  17. Ziegler, Hendrik; Welker, Christian; Sterk, Marco; Haarer, Jan; Rammensee, Hans-Georg; Handgretinger, Rupert; Schilbach, Karin (2014). "Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αβT Cells". Frontiers in Immunology. 5: 645. doi:10.3389/fimmu.2014.00645. ISSN 1664-3224. PMC 4329445. PMID 25709606.
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