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Critical Reviews™ in Immunology
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ISSN Print: 1040-8401
ISSN Online: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2020034838
pages 225-235

Aleatory Epitope Recognition Prevails in Human T Cell Responses?

Paul V. Lehmann
Research and Development Department, Cellular Technology Limited (CTL), Shaker Heights, OH, 44122
Alexander A. Lehmann
Research and Development Department, Cellular Technology Limited (CTL), Shaker Heights, OH, 44122


Eli Sercarz pioneered epitope recognition by T cells. Studying mice, he made the seminal observation decades ago that epitope dominance is so unpredictable with mixed MHC haplotypes that he coined it aleatory, for dice-like. Accordingly, for every individual there is a unique potential epitope space that is defined by the polymorphic and polygenic MHC molecules (restriction elements) expressed. Of this potential epitope space, some peptides will elicit stronger T cell responses than others, bringing about the actually realized epitope space. The selection of the actually recognized peptides from the potential epitope space is random, however, resulting in unique epitope dominance and hierarchy patterns in individuals. Engaging in brute-force epitope scans, which permit the assessment of the entire potential epitope space at the highest possible resolution, we observe aleatory epitope recognition in human CD8 cell responses to viruses. Because the selection of peptide has fundamental implications for successful T cell immune monitoring, we dedicate this article to Eli Sercarz in a special issue of Critical Reviews in Immunology in his honor.


  1. Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729-66.

  2. Moudgil KD, Wang J, Yeung VP, Sercarz EE. Heterogeneity of the T-cell response to immunodominant determinants within hen eggwhite lysozyme of individual syngeneic hybrid F1 mice: Implications for autoimmunity and infection. J Immunol. 1998;161:6046-53.

  3. Sercarz EE. The architectonics of immune dominance: The aleatory effects of molecular position on the choice of antigenic determinants. Chem Immunol. 1989;46:169-85.

  4. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358:155-7.

  5. Targoni OS, Lehmann PV. Endogenous myelin basic protein inactivates the high avidity T-cell repertoire. J Exp Med. 1998;187:2055-63.

  6. Anthony DD, Valdez H, Post AB, Carlson NL, Heeger PS, Lehmann PV. Comprehensive determinant mapping of the hepatitis C-specific CD8 cell repertoire reveals unpredicted immune hierarchy. Clin Immunol. 2002;103:264-76.

  7. Brennick CA, George MM, Srivastava PK, Karandikar SH. Prediction of cancer neoepitopes needs new rules. Sem Immunol. 2020 Feb;47:101387.

  8. Czerkinsky CC, Nilsson LA, Nygren H, Ouchterlony O, Tarkowski A. A solid-phase enzyme-linked Immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods. 1983;65:109-21.

  9. Sedgwick JD, Holt PG. A solid-phase immunoenzymatic technique for the enumeration of specific antibody-secreting cells. J Immunol Methods. 1983;57:301-9.

  10. Wahlgren M, Arnebrant T. Protein adsorption to solid surfaces. Trends Biotechnol. 1991;9:201-8.

  11. Weiss AJ. Overview of membranes and membrane plates used in research and diagnostic ELISPOT assays. Methods Mol Biol. 2012;792:243-56.

  12. Zhang W, Caspell R, Karulin AY, Ahmad M, Haicheur N, Abdelsalam A, Johannesen K, Vignard V, Dudzik P, Georgakopoulou K, Mihaylova A, Silina K, Aptsiauri N, Adams V, Lehmann PV, McArdle S. ELISPOT assays provide reproducible results among different laboratories for T-cell immune monitoring-even in hands of ELISPOT-inexperienced investigators. J Immunotoxicol. 2009;6:227-34.

  13. Czerkinsky C, Andersson G, Ekre H-P, Nilsson L-A, Klareskog L, Ouchterlony O. Reverse ELISPOT assay for clonal analysis of cytokine production I. Enumeration of gamma-interferon-secreting cells. J Immunol Methods. 1988;110:29-36.

  14. Lehmann PV, inventor; Case Western Reserve University, assignee. Methods for measuring T-cell cytokines. United States patent 6410252. 1995 Dec 22.

  15. Forsthuber T, Yip HC, Lehmann PV. Induction of TH1 and TH2 immunity in neonatal mice. Science. 1996;271:1728-30.

  16. Romero P, Cerottini JC, Speiser DE. The human T cell response to melanoma antigens. Adv Immunol. 2006;92:187-224.

  17. Hesse MD, Karulin AY, Boehm BO, Lehmann PV, Tary-Lehmann M. A T-cell clone's avidity is a function of its activation state. J Immunol. 2001;167:1353-61.

  18. Hanson J, Sundararaman S, Caspell R, Karacsony E, Karulin AY, Lehmann PV. ELISPOT assays in 384-well format: Up to 30 data points with one million cells. Cells. 2015;4:71-83.

  19. Zhang W, Lehmann PV. Objective, user-independent ELISPOT data analysis based on scientifically validated principles. Methods Mol Bio. 2012;792:155-71.

  20. Lehmann PV, Zhang W. Unique strengths of ELISPOT for T-cell diagnostics. Methods Mol Bio. 2012;792:3-23.

  21. Lehmann PV, Suwansaard M, Zhang T, Roen DR, Kirchenbaum GA, Karulin AY, Lehmann A, Reche PA. Comprehensive evaluation of the expressed CD8+ T-cell epitope space using high-throughput epitope mapping. Front Immunol. 2019;10:655-68.

  22. Pamer E, Cresswell P. Mechanisms of MHC class I-restricted antigen processing. Ann Rev Immunol. 1998;16:323-58.

  23. Maizels RM, Clarke JA, Harvey MA, Miller A, Sercarz EE. Epitope specificity of the T-cell proliferative response to lysozyme: Proliferative T-cells react predominantly to different determinants from those recognized by B cells. Eur J Immunol. 1980;10:509-15.

  24. Cresswell P. Invariant chain structure and MHC class II function. Cell. 1996;84:505-7.

  25. Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, Sissons JG. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: Frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol. 1996;70:7569-79.

  26. Currier JR, Kuta EG, Turk E, Earhart LB, Loomis-Price L, Janetzki S, Ferrari G, Birx DL, Cox JH. A panel of MHC class I restricted viral peptides for use as a quality control for vaccine trial ELISPOT assays. J Immunol Methods. 2002;260:157-72.

  27. Moldovan I, Targoni O, Zhang W, Sundararaman S, Lehmann PV. How frequently are predicted peptides actually recognized by CD8 cells? Cancer Immunol Immunother. 2016;65:847-55.

  28. Hanson J, Roen DR, Lehmann PV. Four color ImmunoSpot assays for identification of effector T-cell lineages. Methods Mol Bio. 2018;1808:51-62.

  29. Anthony DD, Lehmann PV. T-cell epitope mapping using the ELISPOT approach. Methods. 2003;29:260-9.

  30. Przybyla A, Zhang T, Li R, Roen DR, Mackiewicz A, Lehmann PV. Natural T cell autoreactivity to melanoma antigens: Clonally expanded melanoma-antigen specific CD8 + memory T cells can be detected in healthy humans. Cancer Immunol Immunother. 2019;68:709-20.

  31. Zhang W, Moldovan I, Targoni OS, Subbramanian RA, Lehmann PV. How much of virus-specific CD8 T cell reactivity is detected with a peptide pool when compared to individual peptides? Viruses. 2012;4:2636-49.

  32. La Jolla Institute for Immunology. Detailed analysis of immune response to SARS-CoV-2 bodes well for COVID-19 vaccine. MedicalXpress [Internet]. 2020 May 15 [cited 2020 May 19]. Available from:

  33. Schiller A, Zhang T, Li R, Duechting A, Sundararaman S, Przybyla A, Kuerten S, Lehmann PV. A positive control for detection of functional CD4 T cells in PBMC: The CPI pool. Cells. 2017;6:47-58.

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