Сhain-centricity of TCR phenomenon – opportunities and problems of application in medicine

Abstract

Crystallographic studies of TCR interactions with MHC molecules formed the general conception that a TCR acquire diagonal orientation on an MHC molecule to provide interaction of an antigen peptide, presented by this MHC molecule with the most variable CDR3 regions of α- and β-chains of the TCR. Using alanine mutagenesis, X-ray crystallography, and methods of plasmon resonance researches demonstrated that amino acid residues of the peptide, α-helices and β-sheets of MHC that form the peptide-binding groove, and all three variable regions of both TCR chains take part in TCR-MHC/peptide interaction. Recent studies reveal a novel unusual mode of the specific recognition of HLA/peptide complexes by TCRs. The unique feature of such recognition is in the leading role of the α-chain TCR in interaction with HLA/ peptide while the β-chain TCR plays a passive role, influencing the overall avidity of the TCR-MHC interaction but not its specificity. Such an unusual way of recognition could completely change the practical application of T-cell receptors in medicine. The possibility to identify one TCR chain, dictating the specificity allowed us to avoid long-term and labor-consuming T-cell cloning and apply NGS-sequencing to analyze α-chains in the polyclonal populations of T-cell and their response to the antigen. This approach could significantly fasten selection of therapeutic α-chains and open perspectives for personalized therapy for cancer patients and operative formation of immune resistance to infections.

Keywords:T-cell receptor; TCR α-chain; transgenesis; retroviral transduction; adoptive immunotherapy; antitumor immunity; anti-infectious immunity

For citation: Kazansky D.B., Kalinina A.A., Zamkova M.A., Khromykh L.M., Persiyantseva N.A. Chain-centricity of TCR phenomenon - opportunities and problems of application in medicine. Immunologiya. 2020; 41 (5): 421-31. DOI: https://doi.org/10.33029/0206-4952-2020-41-5-421-431 (in Russian)

Funding. The study was supported by Russian Foundation for Advanced Research Projects. Contract No. 6/053/2015-2018; October 20, 2015.

Conflict of interests. The authors declare no conflict of interests.

References

1. Ding Y.H., Smith K.J., Garboczi D.N., Utz U., Biddison W.E., Wiley D.C. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity. 1998; 8 (4): 403–11. DOI: https://doi.org/10.1016/s1074-7613(00)80546-4

2. Garcia K.C., Degano M., Pease L.R., Huang M., Peterson P.A., Teyton L., Wilson I.A. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science. 1998; 279 (5354): 1166–72. DOI: https://doi.org/10.1126/science.279.5354.1166

3. Reiser J.B., Darnault C., Grégoire C., Mosser T., Mazza G., Kearney A., van der Merwe P.A., Fontecilla-Camps J.C., Housset D., Malissen B. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 2003; 4 (3): 241–7. DOI: https://doi.org/10.1038/ni891

4. Sant’Angelo D.B., Waterbury G., Preston-Hurlburt P., Yoon S.T., Medzhitov R., Hong S.C., Janeway C.A. Jr. The specificity and orientation of a TCR to its peptide-MHC class II ligands. Immunity. 1996; 4 (4): 367–76. DOI: https://doi.org/10.1016/s1074-7613(00)80250-2

5. Schuhbauer D., Müller B., Mitchison A. Unrepresentative behavior of T cell receptor-transgenic CD4+ T cells upon adoptive transfer: lack of need for priming and an extended booster dose-response. Immunobiology. 1996; 195 (2): 152–9. DOI: https://doi.org/10.1016/S0171-2985(96)80035-0

6. Zvezdova E.S., Silaeva Yu.Yu., Vagida M.S., Maryukhnich E.V., Deykin A.V., Ermolkevich T.G., Kadulin S.G., Sadchikova E.R., Gol’dman I.L., Kazanskiy D.B. Generation of transgenic animals, expressing alpha- and beta-chains of autoreactive TCR. Molekulyarnaya biologiya. 2010; 44 (2): 311–22. (in Russian)

7. Silaeva Y.Y., Kalinina A.A., Vagida M.S., Khromykh L.M., Deykin A.V., Ermolkevich T.G., Sadchikova E.R., Gol’dman I.L., Kazanskiy D.B. Decrease in pool of T lymphocytes with surface phenotypes of effector and central memory cells under influence of TCR transgenic β-chain expression. Biockhimiya. 2013; 78 (5): 714–26. (in Russian)

8. Zamkova M., Kalinina A., Silaeva Y., Persiyantseva N., Bruter A., Deikin A., Khromykh L., Kazansky D. Dominant role of the α-chain in rejection of tumor cells bearing a specific alloantigen in TCRα transgenic mice and in in vitro experiments. Oncotarget. 2019; 10 (47): 4808–21. DOI: https://doi.org/10.18632/oncotarget.27093

9. Miller J.F. Discovering the origins of immunological competence. Annu. Rev. Immunol. 1999; 17: 1–17. DOI: https://doi.org/10.1146/annurev.immunol.17.1.1

10. Irving B.A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991; 64 (5): 891–901. DOI: https://doi.org/10.1016/0092-8674(91)90314-o

11. Call M.E., Wucherpfennig K.W. Molecular mechanisms for the assembly of the T cell receptor-CD3 complex. Mol. Immunol. 2004; 40 (18): 1295–305. DOI: https://doi.org/10.1016/j.molimm.2003.11.017

12. Natarajan K., Jiang J., May N.A., Mage M.G., Boyd L.F., McShan A.C., Sgourakis N.G., Bax A., Margulies D.H. The role of molecular flexibility in antigen presentation and T cell receptor-mediated signaling. Front. Immunol. 2018; 9: 1657. DOI: https://doi.org/10.3389/fimmu.2018.01657

13. Ciofani M., Knowles G.C., Wiest D.L., von Boehmer H., Zúñiga-Pflücker J.C. Stage-specific and differential Notch dependency at the alphabeta and gammadelta T lineage bifurcation. Immunity. 2006; 25 (1): 105–16. DOI: https://doi.org/10.1016/j.immuni.2006.05.010

14. He X., Janeway C.A. Jr., Levine M., Robinson E., Preston-Hurlburt P., Viret C., Bottomly K. Dual receptor T cells extend the immune repertoire for foreign antigens. Nat. Immunol. 2002; 3 (2): 127–34. DOI: https://doi.org/10.1038/ni751

15. Legrand N., Freitas A.A. CD8+ T lymphocytes in double alpha beta TCR transgenic mice. II. Competitive fitness of dual alpha beta TCR CD8+ T lymphocytes in the peripheral pools. J. Immunol. 2001; 167 (11): 6158–64. DOI: https://doi.org/10.4049/jimmunol.167.11.6158

16. Szondy Z., Garabuczi É., Tóth K., Kiss B., Köröskényi K. Thymocyte death by neglect: contribution of engulfing macrophages. Eur. J. Immunol. 2012; 42 (7): 1662–7.

17. Anderson M.S., Su M.A. Aire and T cell development. Curr. Opin. Immunol. 2011; 23 (2): 198–206. DOI: https://doi.org/10.1016/j.coi.2010.11.007

18. Van Laethem F., Tikhonova A.N., Pobezinsky L.A., Tai X., Kimura M.Y., Le Saout C., Guinter T.I., Adams A., Sharrow S.O., Bernhardt G., Feigenbaum L., Singer A. Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell. 2013; 154 (6): 1326–41. DOI: https://doi.org/10.1016/j.cell.2013.08.009

19. Xiong Y., Bosselut R. CD4-CD8 differentiation in the thymus: connecting circuits and building memories. Curr. Opin. Immunol. 2012; 24 (2): 139–45. DOI: https://doi.org/10.1016/j.coi.2012.02.002

20. Pobezinskiy L.A., Pobezinskaya E.L., Tereshchenko T.S., Chervonskiy A.V., Kazanskiy D.B. Peripheral pool of CD8+ T-cells contains lymphocytes with antigen-specific receptors that recognize syngeneic MHC class II molecules. Ontogenez. 2004; 35 (3): 183–9. (in Russian)

21. Singer A., Adoro S., Park J.H. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat. Rev. Immunol. 2008; 8 (10): 788–801. DOI: https://doi.org/10.1038/nri2416

22. Surh C.D., Sprent J. Homeostasis of naive and memory T cells. Immunity. 2008; 29 (6): 848–62. DOI: https://doi.org/10.1016/j.immuni.2008.11.002

23. Bains I., Yates A.J., Callard R.E. Heterogeneity in thymic emigrants: implications for thymectomy and immunosenescence. PLoS One. 2013; 8 (2): e49554. DOI: https://doi.org/10.1371/journal.pone.0049554

24. Kazanskiy D.B., Petrishchev V.N., Shtil’ A.A., Chernysheva A. D., Sernova N.V., Abronina I.F., Pobezinskiy L.A., Agafonova E.L. Heat shock of antigen-presenting cells as a method for functional testing of the cells of allospecific memory. Bioorganicheskaya khimiya. 1999; 25 (2): 117–28. (in Russian)

25. Kazanskiy D.B., Chernysheva A.D., Sernova N.V., Petrishchev V.N., Pobezinskiy L.A., Agafonova E.L., Chervonskiy A.V. The nature of epitopes, recognized by T-lymphocytes in the allogenic immune response. Molekulyarnaya biologiya. 1998; 32 (4): 692–702. (in Russian)

26. Grinenko T.S., Pobezinskaya E.L., Pobezinskiy L.A., Baturina I.A., Zvezdova E.S., Kazanskiy D.B. Suppression of primary allogenic response by CD8+ memory cells. Byulleten’ eksperimental’noi biologii i meditsiny. 2005; 140: 545–9. (in Russian)

27. Pobezinskaya E.L., Pobezinskiy L.A., Silaeva Y.Y., Anfalova T.V., Khromykh L.M., Tereshchenko T.S., Zvezdova E.S., Kazanskiy D.B. Cross reactivity of T cell receptor on memory CD8+ cells isolated after immunization with allogeneic tumor cells. Byulleten’ eksperimental’noi biologii i meditsiny. 2004; 137: 563–8. (in Russian)

28. Perkins D.L., Listman J.A., Wang Y., Ho S.S., Finn P.W., Rimm I.J. Differential expression of activation markers during tolerance induction by superantigens in T-cell receptor (beta-chain) transgenic mice. Cell. Immunol. 1994; 156 (2): 310–21. DOI: https://doi.org/10.1006/cimm.1994.1177

29. Fassò M., Anandasabapathy N., Crawford F., Kappler J., Fathman C.G., Ridgway W.M. T cell receptor (TCR)-mediated repertoire selection and loss of TCR vbeta diversity during the initiation of a CD4(+) T cell response in vivo. J. Exp. Med. 2000; 192 (12): 1719–30. DOI: https://doi.org/10.1084/jem.192.12.1719

30. Nakatsugawa M., Yamashita Y., Ochi T., Tanaka S., Chamoto K., Guo T., Butler M.O., Hirano N. Specific roles of each TCR hemichain in generating functional chain-centric TCR. J. Immunol. 2015; 194 (7): 3487–500. DOI: https://doi.org/10.4049/jimmunol.1401717

31. Ochi T., Nakatsugawa M., Chamoto K., Tanaka S., Yamashita Y., Guo T., Fujiwara H., Yasukawa M., Butler M.O., Hirano N. Optimization of T-cell reactivity by exploiting TCR chain centricity for the purpose of safe and effective antitumor TCR gene therapy. Cancer. Immunol. Res. 2015; 3 (9): 1070–81. DOI: https://doi.org/10.1158/2326-6066.CIR-14-0222

32. Nakatsugawa M., Rahman M.A., Yamashita Y., Ochi T., Wnuk P., Tanaka S., Chamoto K., Kagoya Y., Saso K., Guo T., Anczurowski M., Butler M.O, Hirano N. CD4(+) and CD8(+) TCRβ repertoires possess different potentials to generate extraordinarily high-avidity T cells. Sci. Rep. 2016; 6: 23821. DOI: https://doi.org/10.1038/srep23821

33. Guo T., Ochi T., Nakatsugawa M., Kagoya Y., Anczurowski M., Wang C.H., Rahman M.A., Saso K., Butler M.O., Hirano N. Generating de novo antigen-specific human T cell receptors by retroviral transduction of centric hemichain. J. Vis. Exp. 2016; 116: 54697. DOI: https://doi.org/10.3791/54697

34. Kazansky D.B. Intrathymic selection: new insight into tumor immunology. Adv. Exp. Med. Biol. 2007; 601: 133–44. doi: DOI: https://doi.org/10.1007/978-0-387-72005-0_14

35. Kazansky D.B. MHC restriction and allogeneic immune responses. J. Immunotoxicol. 2008; 5 (4): 369–84. DOI: https://doi.org/10.1080/15476910802476708

36. Egorov E.S., Merzlyak E.M., Shelenkov A.A., Britanova O.V., Sharonov G.V., Staroverov D.B., Bolotin D.A., Davydov A.N., Barsova E., Lebedev Y.B., Shugay M., Chudakov D.M. Quantitative profiling of immune repertoires for minor lymphocyte counts using unique molecular identifiers. J. Immunol. 2015; 194 (12): 6155–63.

37. Shugay M., Britanova O.V., Merzlyak E.M., Turchaninova M.A., Mamedov I.Z., Tuganbaev T.R., Bolotin D.A., Staroverov D.B., Putintseva E.V., Plevova K., Linnemann C., Shagin D., Pospisilova S., Lukyanov S., Schumacher T.N., Chudakov D.M. Towards error-free profiling of immune repertoires. Nat. Methods. 2014; 11 (6): 653–55.

38. Bolotin D.A., Poslavsky S., Mitrophanov I., Shugay M., Mamedov I.Z., Putintseva E.V., Chudakov D.M. MiXCR: software for comprehensive adaptive immunity profiling. Nat. Methods. 2015; 2 (5): 380–1.

39. Kazanskiy D.B., Khromykh L.M., Kalinina A.A., Silaeva Yu.Yu., Zamkova M.A., Bruter A.V., Persiyantseva N.A., Chikileva I.O., Dzholokhava L.K., Nesterenko L.N., Sobyanin K.A., Knyazhanskaya E.S. Method for creating anti-infectious immunological protection against Salmonella typhimurium and Listeria monocytogenes using transgenesis of T-lymphocytes. Patent No. RU 2706554. Russia, 2019. (in Russian)

40. Mitin A.N., Litvina M.M., Komogorova V.V., Sharova N.I., Yarilin A.A. Contribution of homeostatic proliferation and related proceses to restoration of peripheral T cell population in iradiation induced lymphopenia. Immunologiya. 2013; 34 (5): 242–7. (in Russian)

41. Mitin A.N., Litvina M.M., Komogorova V.V., Shevelev S.V., Sharova N.I., Yarilin A.A. Phenotypic conversion of naive T-cells in central memory T-cells after adoptive transfer to sublethally irradiated mice. Immunologiya. 2014; 35 (4): 225–9. (in Russian)

42. Silaeva Y.Y., Grinenko T.S., Vagida M.S., Kalinina A.A., Khromykh L.M., Kazansky D.B. Immune selection of tumor cells in TCR β-chain transgenic mice. J. Immunotoxicol. 2014; 11 (4): 393–9. DOI: https://doi.org/10.3109/1547691X.2013.861548

43. Kalinina A.A., Silaeva Y.Y., Kazanskiy D.B., Khromykh L.M. The Role of Recombinant Human Cyclophilin A in the Antitumor Immune Response. Acta Naturae. 2019; 11 (2): 63–7. DOI: https://doi.org/10.32607/20758251-2019-11-2-63-67 (in Russian)

44. Kiselevskiy M.V., Chikileva I.O., Sitdikova S.M., Vlasenko R.Ya., Karaulov A.V. Prospectives of application of the genetically modified lymphocytes with chimeric T-cell receptor (CAR-T-cells) for the therapy of solid tumors. Immunologiya. 2019; 40 (4): 48–55. (in Russian)

45. Rosenberg S.A., Restifo N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015; 348 (6230): 62–8. DOI: https://doi.org/10.1126/science.aaa4967

46. Yamamoto T.N., Kishton R.J., Restifo N.P. Developing neoantigen-targeted T cell-based treatments for solid tumors. Nat. Med. 2019; 25 (10): 1488–99. DOI: https://doi.org/10.1038/s41591-019-0596-y

47. Yang Y., Kohler M.E., Chien C.D., Sauter C.T., Jacoby E., Yan C., Hu Y., Wanhainen K., Qin H., Fry T.J. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci. Transl. Med. 2017; 9 (417): eaag1209. DOI: https://doi.org/10.1126/scitranslmed.aag1209

48. Blichfeldt E., Munthe L.A., Røtnes J.S., Bogen B. Dual T cell receptor T cells have a decreased sensitivity to physiological ligands due to reduced density of each T cell receptor. Eur. J. Immunol. 1996; 26 (12): 2876–84. DOI: https://doi.org/10.1002/eji.1830261211

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»