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词条 T cell receptor revision
释义

  1. Background of T cell specificity regulation

  2. Evidence for TCR revision

  3. References

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 autoractive 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. ^{{Cite journal|title = 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 = Journal of Immunology|date = Apr 1, 2003|issn = 0022-1767|pmid = 12646605|pages = 3455–3459|volume = 170|issue = 7|first = Gisela M.|last = Vaitaitis|first2 = Michelle|last2 = Poulin|first3 = Richard J.|last3 = Sanderson|first4 = Kathryn|last4 = Haskins|first5 = David H.|last5 = Wagner|doi=10.4049/jimmunol.170.7.3455}}
2. ^{{Cite journal|title = Modulation of TCRβ surface expression during TCR revision|journal = Cellular Immunology|date = 2012|issn = 1090-2163|pmc = 3244515|pmid = 22138498|pages = 124–129|volume = 272|issue = 2|doi = 10.1016/j.cellimm.2011.10.022|first = Kalynn B.|last = Simmons|first2 = Maramawit|last2 = Wubeshet|first3 = Kristina T.|last3 = Ames|first4 = Catherine J.|last4 = McMahan|first5 = J. Scott|last5 = Hale|first6 = Pamela J.|last6 = Fink}}
3. ^{{Cite journal|title = Receptor revision in T cells: an open question?|journal = Trends in Immunology|date = Jun 2004|issn = 1471-4906|pmid = 15145316|pages = 276–279|volume = 25|issue = 6|doi = 10.1016/j.it.2004.04.001|first = Raul|last = Mostoslavsky|first2 = Frederick W.|last2 = Alt}}
4. ^{{Cite journal|title = Re-shaping the T cell repertoire: TCR editing and TCR revision for good and for bad|journal = Clinical Immunology (Orlando, Fla.)|date = Apr 2007|issn = 1521-6616|pmid = 16990051|pages = 1–6|volume = 123|issue = 1|doi = 10.1016/j.clim.2006.08.006|first = David H.|last = Wagner}}
5. ^1 {{Cite journal|title = T-cell receptor revision: friend or foe?|journal = Immunology|date = Apr 2010|issn = 1365-2567|pmc = 2842493|pmid = 20201984|pages = 467–473|volume = 129|issue = 4|doi = 10.1111/j.1365-2567.2010.03250.x|first = J. Scott|last = Hale|first2 = Pamela J.|last2 = Fink}}
6. ^{{Cite journal|title = Cutting edge: TCR revision occurs in germinal centers|journal = Journal of Immunology|date = Dec 1, 2004|issn = 0022-1767|pmid = 15557142|pages = 6532–6536|volume = 173|issue = 11|first = Cristine J.|last = Cooper|first2 = Gail L.|last2 = Turk|first3 = Mingyi|last3 = Sun|first4 = Andrew G.|last4 = Farr|first5 = Pamela J.|last5 = Fink|doi=10.4049/jimmunol.173.11.6532}}
7. ^{{Cite journal|title = Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions|journal = Proceedings of the National Academy of Sciences of the United States of America|date = Apr 15, 2014|issn = 1091-6490|pmc = 3992682|pmid = 24706795|pages = 5652–5657|volume = 111|issue = 15|doi = 10.1073/pnas.1321803111|first = Lauren E.|last = Higdon|first2 = Katherine A.|last2 = Deets|first3 = Travis J.|last3 = Friesen|first4 = Kai-Yin|last4 = Sze|first5 = Pamela J.|last5 = Fink}}
8. ^{{Cite journal|title = Dual receptor T cells extend the immune repertoire for foreign antigens|journal = Nature Immunology|date = Feb 2002|issn = 1529-2908|pmid = 11812989|pages = 127–134|volume = 3|issue = 2|doi = 10.1038/ni751|first = Xin|last = He|first2 = Charles A.|last2 = Janeway|first3 = Matthew|last3 = Levine|first4 = Eve|last4 = Robinson|first5 = Paula|last5 = Preston-Hurlburt|first6 = Christophe|last6 = Viret|first7 = Kim|last7 = Bottomly}}
9. ^{{Cite journal|title = Cutting edge: Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease|journal = Journal of Immunology|date = Jun 1, 2009|issn = 1550-6606|pmc = 3196624|pmid = 19454656|pages = 6639–6643|volume = 182|issue = 11|doi = 10.4049/jimmunol.0900638|first = Gerald P.|last = Morris|first2 = Paul M.|last2 = Allen}}
10. ^{{Cite journal|title = The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires|journal = Journal of Immunology|date = Aug 15, 2014|issn = 1550-6606|pmc = 4119549|pmid = 25015825|pages = 1778–1786|volume = 193|issue = 4|doi = 10.4049/jimmunol.1400532|first = Peggy P.|last = Ni|first2 = Benjamin|last2 = Solomon|first3 = Chyi-Song|last3 = Hsieh|first4 = Paul M.|last4 = Allen|first5 = Gerald P.|last5 = Morris}}
11. ^{{Cite journal| issn = 1074-7613| volume = 9| issue = 5| pages = 637–647| last1 = McMahan| first1 = C. J.| last2 = Fink| first2 = P. J.| title = RAG reexpression and DNA recombination at T cell receptor loci in peripheral CD4+ T cells| journal = Immunity|date=November 1998| pmid = 9846485| doi=10.1016/s1074-7613(00)80661-5}}
12. ^{{Cite journal|title = Superantigen-induced TCR alpha locus secondary rearrangement: role in tolerance induction|journal = Journal of Immunology|date = Apr 1, 2002|issn = 0022-1767|pmid = 11907080|pages = 3259–3265|volume = 168|issue = 7|first = Ching-Yu|last = Huang|first2 = Rachel|last2 = Golub|first3 = Gillian E.|last3 = Wu|first4 = Osami|last4 = Kanagawa|doi=10.4049/jimmunol.168.7.3259}}
13. ^1 {{Cite journal|title = Age-dependent TCR revision mediated by interaction between alphabeta TCR and self-antigens|journal = Journal of Immunology|date = Aug 15, 2007|issn = 0022-1767|pmid = 17675475|pages = 2163–2169|volume = 179|issue = 4|first = Mitsuyo|last = Takase|first2 = Edith M.|last2 = Kanagawa|first3 = Osami|last3 = Kanagawa|doi=10.4049/jimmunol.179.4.2163}}
14. ^{{Cite journal|title = T cells from epicutaneously immunized mice are prone to T cell receptor revision|journal = Proceedings of the National Academy of Sciences of the United States of America|date = Feb 22, 2005|issn = 0027-8424|pmc = 549496|pmid = 15708975|pages = 2898–2903|volume = 102|issue = 8|doi = 10.1073/pnas.0409880102|first = Margaret S.|last = Bynoe|first2 = Christophe|last2 = Viret|first3 = Richard A.|last3 = Flavell|first4 = Charles A.|last4 = Janeway}}
15. ^{{Cite journal|title = An in vitro model of T cell receptor revision in mature human CD8+ T cells|journal = Molecular Immunology|date = Jan 2008|issn = 0161-5890|pmid = 17659780|pages = 328–337|volume = 45|issue = 2|doi = 10.1016/j.molimm.2007.06.153|first = Erica|last = Lantelme|first2 = Luca|last2 = Orlando|first3 = Paola|last3 = Porcedda|first4 = Valentina|last4 = Turinetto|first5 = Mario|last5 = De Marchi|first6 = Antonio|last6 = Amoroso|first7 = Stefania|last7 = Mantovani|first8 = Claudia|last8 = Giachino}}
16. ^{{Cite journal|title = Cutting edge: TCR revision affects predominantly Foxp3 cells and skews them toward the Th17 lineage|journal = Journal of Immunology|date = Nov 1, 2007|issn = 0022-1767|pmc = 2776039|pmid = 17947636|pages = 5653–5657|volume = 179|issue = 9|first = Dietmar|last = Zehn|first2 = Michael J.|last2 = Bevan|first3 = Pamela J.|last3 = Fink|doi=10.4049/jimmunol.179.9.5653}}
17. ^{{Cite journal|title = Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αβT Cells|journal = Frontiers in Immunology|date = 2014|issn = 1664-3224|pmc = 4329445|pmid = 25709606|pages = 645|volume = 5|doi = 10.3389/fimmu.2014.00645|first = Hendrik|last = Ziegler|first2 = Christian|last2 = Welker|first3 = Marco|last3 = Sterk|first4 = Jan|last4 = Haarer|first5 = Hans-Georg|last5 = Rammensee|first6 = Rupert|last6 = Handgretinger|first7 = Karin|last7 = Schilbach}}

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