Abstract
A workshop group developed the concept of a “polyspecific” TCR/BCR in the framework of today’s consensus model. They argue that the individual TCR/BCR combining site is composed of a packet of specificities randomly plucked from the repertoire, hence it is “polyspecific.” This essay analyzes the conclusions of the workshop and suggests an alternative. “Polyspecificity” must be dissected into its two component parts, specificity and degeneracy. The TCR and the BCR must be treated differently because the TCR recognizes allele-specifically the MHC-encoded restricting element (R) that serves as the platform presenting peptide (P). Only the anti-P paratope of the TCR behaves analogously to the BCR paratope. The two paratopes are selected to recognize a shape-determinant referred to as an epitope or ligand. The paratope is functionally unispecific in recognition, not polyspecific, with respect to shape; it is degenerate in recognition with respect to chemistry. The recognized shape-determinant can be the product of many chemically different substances, peptide, carbohydrate, lipid, steroid, nucleic acid, etc. Such a degenerate set is functionally treated by the paratope as one shape/epitope/ligand and, in no sense, can a paratope recognizing such a degenerate set be described as “polyspecific.” Degeneracy and specificity are concepts that must be distinguished. The two positions are analyzed in this essay, the experiments used to support the view that the paratope of the TCR/BCR is polyspecific, are reinterpreted, and an alternative framework with its accompanying nomenclature, is presented.
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References
Wucherpfennig KW, Allen PM, Celada F, et al. Polyspecificity of T cell and B cell receptor recognition. Sem Immunol 2007;19:216–224.
Matzinger P, Bevan MJ. Hypothesis. Why do so many lymphocytes respond to major histocompatibility antigens? Cellular Immunol 1977;29:1–5.
Langman RE, Cohn M. The Standard Model of T-cell receptor function: a critical reassessment. Scand J Immunol 1999;49:570–7.
Cohn M. The Tritope model of restrictive recognition by the TCR. Trends Immunol 2003;24:127–31.
Cohn M. Distinguishing the Tritope from the interaction antigen models. Trends Immunol 2004;25:8–9.
Cohn M. The Tritope Model for restrictive recognition of antigen by T-cells: I. What assumptions about structure are needed to explain function? Mol Immunol 2005;42:1419–43.
Cohn M. The Tritope Model for restrictive recognition of antigen by T-cells: II. Implications for ontogeny, evolution and physiology. Mol Immunol 2007;in press.
Garboczi DN, Ghosh P, Utz U, et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 1996;384:134–41.
Garcia KD, Degano M, Stanfield RL. An alpha-beta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 1996;274:209–19.
Langman RE. The specificity of immunological reactions. Mol Immunol 2000;37:555–61.
Cohn M. A new concept of immune specificity emerges from a consideration of the self-nonself discrimination. Cell Immunol 1997;181:103–8.
Cohn M. At the feet of the Master: the search for universalities. Divining the evolutionary selection pressures that resulted in an immune system. Cytogenet Cell Genet 1998;80:54–60.
Cohn M. The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs. Immunol Revs 2002;185:24–38.
Landsteiner K. The specificity of serological reactions. Cambridge: Harvard University Press; 1945.
Lederberg J. Genes and antibodies. Science 1959;129:1649–53.
Talmage DW. Immunological specificity: an alternative to the classical concept. Science 1959;129:1643–48.
Cohn M. Logic of the self-nonself discrimination: principles and history. In: Cambrosio A, Moulin A, editors. Dialogues with selves historical issues and contemporary debates in immunology. France: Editions Elsevier; 2001. p. 53–85.
Langman RE, Cohn M. The E-T (elephant-tadpole) paradox necessitates the concept of a unit of B-cell function: the Protecton. Mol Immunol 1987;24:675–97.
Cohn M, Langman RE. The Protecton: the evolutionarily selected unit of humoral immunity. Immunol Rev 1990;115:1–131.
Cohn M. What are the commonalities governing the behavior of humoral immune recognitive repertoires? Dev Comp Immunol 2006;30:19–42.
Cohn M. Degeneracy, mimicry and crossreactivity in immune recognition. Mol Immunol 2005;42:651–5.
Cohn M. Conceptualizing the self-nonself discrimination by the vertebrate immune system. In: Timmis J, Flower D, editors. In silico immunology. New York: Springer; 2007. p. 375–98.
Cohn M. A biological context for the self-nonself discrimination and the regulation of effector class by the immune system. Immunol Res 2005;31:133–50.
Cohn M. The common sense of the self-nonself discrimination. Springer Semin Immunopathol 2005;27:3–17.
Cohn M. The self-nonself discrimination: reconstructing a cabbage from sauerkraut. Res Immunol 1992;143:323–34.
Bevan M. Killer cells reactive to altered-self antigens can also be alloreactive. Proc Natl Acad Sci USA 1977;74:2094–8.
Hunig TR, Bevan MJ. Antigen recognition by cloned cytotoxic T lymphocytes follows rules predicted by the altered-self hypothesis. J Exp Med 1982;155:111–25.
Bevan MJ. High determinant density may explain the phenomenon of alloreactivity. Imunol Today 1984;5:128–30.
Nikolich-Zugich J. High specificity, not degeneracy, allows T cell alloresponses. Nat Immunol 2007;8:335–7.
Felix NJ, Donermeyer DL, Horvath S, et al. Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes. Nat Immunol 2007;8:388–97.
Müllbacher A, Lobigs M, Kos FJ, et al. Alloreactive cytotoxic T-cell function, peptide nonspecific. Scand J Immunol 1999;49:563–9.
Rubin B, Gouaillard C, Weideranders G, et al. The IE allogeneic response of T cells from C57B1/6 mice is associated with genes of the TCRa locus. Scand J Immunol 1993;37:388–97.
Ewijk WV, Ron Y, Monaco J, et al. Compartmentalization of MHC Class II gene expression in transgenic mice. Cell 1988;53:357–70.
Viret C, Janeway CA. Functional and phenotypic evidence for presentation of E alpha 52–68 structurally related self-peptide(s) in I-E alpha-deficient mice. J Immunol 2000;164:4627–34.
LaFuse WP, Savariravan S, McCormick JF, et al. Identification of 1-E alpha genes in H-2 recombinant mouse strains by F1 complementation. Transplantation 1987;43:297–301.
Zy-Tmg E, Chu C, Carswell C, et al. The minimal polymorphism of Class II E alpha chains is not due to the functional neutrality of mutations. Genetics 1994;40:9–20.
Chen C, Eisen HN, Kranz DM. A model T-cell receptor system for studying memory T-cell development. Microbes Infect 2003;5:233–40.
Sha WC, Nelson CA, Newberry RD, et al. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 1988;336:73–6.
Capone M, Curnow J, Bouvier G, et al. T cell development in TCR-αβ transgenic mice. J Immunol 1995;154:5165–72.
Dao T, Blander JM, Sant’Angelo DB. Recognition of a specific self-peptide: self-MHC Class II complex is critical for positive selection of thymocytes expressing the D10-TCR. J Immunol 2003;170:48–54.
Huseby ES, White J, Crawford F, et al. How the T cell repertoire becomes peptide and MHC specific. Cell 2005;122:247–60.
Huseby ES, Crawford F, White J, et al. Negative selection imparts peptide specificity to the mature T cell repertoire. PNAS 2003;100:11565–70.
Percus JK, Percus OE, Perelson AS. Predicting the size of the T-cell receptor and antibody combining region from consideration of efficient self-nonself discrimination. Proc Natl Acad Sci USA 1993;90:1691–5.
De Boer RJ, Perelson AS. How diverse should the immune system be? Proc R Soc Scan 1993;B252:171–5.
Nemazee D. Antigen receptor “capacity” and the sensitivity of self-tolerance. Immunol Today 1996;17:25–9.
Notkins AL. Polyreactivity of antibody molecules. Trends Immunol 2004;25:174–9.
Tiegs SL, Russell DM, Nemazee D. Receptor editing in self-reactive bone marrow B cells. J Exp Med 1993;177:1009–20.
Lang J, Jackson M, Teyton L, et al. B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen. J Exp Med 1996;184:1685–97.
Radic MZ, Erikson J, Litwin S, et al. B lymphocytes may escape tolerance by revising their antigen receptors. J Exp Med 1993;177:1165–73.
Gay D, Saunders T, Camper S, et al. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 1993;177:999–1008.
Nemazee D, Weigert M. Revising B cell receptors. J Exp Med 2000;191:1881–94.
Matsuda F, Ishii K, Bourvagnet P, et al. The complete nucleotide sequence of the human heavy chain variable region locus. J Exp Med 1998;188:2151–62.
Zachau HG. The immunoglobulin kappa gene families of human and mouse: a cottage industry approach. Biol Chem 2000;381:951–4.
Cohn M, Langman RE, editors. Haplotype and isotype exclusion: How and Why? Semin Immunol 2002;14:247.
Garcia KC, Degano M, Pease LR, et al. Structural basis of plasticity in T cell receptor recognition of a Self Peptide-MHC antigen. Science 1998;279:1166–72.
Mazza C, Malissen B. What guides MHC-restricted TCR recognition? Sem Immunol 2007;19(4):225–35.
Acknowledgments
This work was supported by a grant (RR07716) from the National Center For Research Resources (NCRR), a component of the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not represent the official view of NCRR or NIH. I wish to thank the FLAD Computational Biology Collaboratorium at the Gulbenkian Institute in Oeiras, Portugal for hosting and providing facilities used to conduct part of this research as a FLAD visiting scholar at the Institute. I appreciate the criticism, enthusiasm and support from the Director, Dr. Antonio Coutinho.
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Cohn, M. An in depth analysis of the concept of “polyspecificity” assumed to characterize TCR/BCR recognition. Immunol Res 40, 128–147 (2008). https://doi.org/10.1007/s12026-007-8003-z
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DOI: https://doi.org/10.1007/s12026-007-8003-z