Dynamics of individual T Cell repertoires: From cord blood to centenarians

Journal of Immunology

Volumn 196, Issue 12, 2016, Pages 5005-5013

  Britanova, Olga V ^a,b,c   Shugay, Mikhail ^a,b,c   Merzlyak, Ekaterina M ^a   Staroverov, Dmitriy B ^a   Putintseva, Ekaterina V ^a   Turchaninova, Maria A ^a,b,c   Mamedov, Ilgar Z ^a,c   Pogorelyy, Mikhail V ^a   Bolotin, Dmitriy A ^a,b,c   Izraelson, Mark ^a,c   Davydov, Alexey N ^c   Egorov, Evgeny S ^a,b,c   Kasatskaya, Sofya A ^a   Rebrikov, Denis V ^b,d   Lukyanov, Sergey ^a,b   Chudakov, Dmitriy M ^a,b,c  

^a SHEMYAKIN OVCHINNIKOV INSTITUTE OF BIOORGANIC CHEMISTRY   (Russian Federation)

^b PIROGOV RUSSIAN NATIONAL RESEARCH MEDICAL UNIVERSITY   (Russian Federation)

^c MASARYK UNIVERSITY   (Czech Republic)

^d VAVILOV INSTITUTE OF GENERAL GENETICS   (Russian Federation)

Author keywords

[No Author keywords available]

Indexed keywords

COMPLEMENTARY DNA; MESSENGER RNA; T LYMPHOCYTE RECEPTOR BETA CHAIN; EPITOPE; LYMPHOCYTE ANTIGEN RECEPTOR;

ADAPTIVE IMMUNITY; ADULT; AGE DISTRIBUTION; AGED; ARTICLE; CELLULAR DISTRIBUTION; CELLULAR IMMUNITY; CHILD; CONTROLLED STUDY; FEMALE; HUMAN; LONGEVITY; LYMPHOCYTE FUNCTION; MAJOR CLINICAL STUDY; MALE; MIDDLE AGED; MOLECULAR DYNAMICS; PRESCHOOL CHILD; PRIORITY JOURNAL; PROTEIN DETERMINATION; PROTEIN FUNCTION; REGULATORY MECHANISM; SCHOOL CHILD; T LYMPHOCYTE; UMBILICAL CORD BLOOD; VERY ELDERLY; ADOLESCENT; AGING; CELL CLONE; CYTOLOGY; FETUS BLOOD; GENETICS; IMMUNOLOGY; PHYSIOLOGY; SOFTWARE; TIME FACTOR; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; AGING; CHILD; CLONE CELLS; FEMALE; FETAL BLOOD; HUMANS; IMMUNODOMINANT EPITOPES; LONGEVITY; MALE; MIDDLE AGED; MOLECULAR DYNAMICS SIMULATION; RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA; SOFTWARE; T-LYMPHOCYTES; TIME FACTORS; YOUNG ADULT;

EID: 84974834896     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1600005     Document Type: Article

References (93)

1. Messaoudi, I., J. Lemaoult, J. A. Guevara-Patino, B. M. Metzner, and J. Nikolich-Zugich. 2004. Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J. Exp. Med. 200: 1347-1358.
2. Goronzy, J. J., and C. M. Weyand. 2005. T cell development and receptor diversity during aging. Curr. Opin. Immunol. 17: 468-475.
3. Naylor, K., G. Li, A. N. Vallejo, W. W. Lee, K. Koetz, E. Bryl, J. Witkowski, J. Fulbright, C. M. Weyand, and J. J. Goronzy. 2005. The influence of age on T cell generation and TCR diversity. J. Immunol. 174: 7446-7452.
4. Goronzy, J. J., W. W. Lee, and C. M. Weyand. 2007. Aging and T-cell diversity. Exp. Gerontol. 42: 400-406.
5. Britanova, O. V., E. V. Putintseva, M. Shugay, E. M. Merzlyak, M. A. Turchaninova, D. B. Staroverov, D. A. Bolotin, S. Lukyanov, E. A. Bogdanova, I. Z. Mamedov, et al. 2014. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192: 2689-2698.
6. Qi, Q., Y. Liu, Y. Cheng, J. Glanville, D. Zhang, J. Y. Lee, R. A. Olshen, C. M. Weyand, S. D. Boyd, and J. J. Goronzy. 2014. Diversity and clonal selection in the human T-cell repertoire. Proc. Natl. Acad. Sci. USA 111: 13139-13144.
7. Yager, E. J., M. Ahmed, K. Lanzer, T. D. Randall, D. L. Woodland, and M. A. Blackman. 2008. Age-Associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J. Exp. Med. 205: 711-723.
8. Arnold, C. R., J. Wolf, S. Brunner, D. Herndler-Brandstetter, and B. Grubeck-Loebenstein. 2011. Gain and loss of T cell subsets in old age-Age-related reshaping of the T cell repertoire. J. Clin. Immunol. 31: 137-146.
9. Buchholz, V. R., M. Neuenhahn, and D. H. Busch. 2011. CD8+ T cell differentiation in the aging immune system: until the last clone standing. Curr. Opin. Immunol. 23: 549-554.
10. OHara, G. A., S. P. Welten, P. Klenerman, and R. Arens. 2012. Memory T cell inflation: understanding cause and effect. Trends Immunol. 33: 84-90.
11. Goronzy, J. J., and C. M. Weyand. 2013. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14: 428-436.
12. Nikolich-Zugich, J. 2014. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J. Immunol. 193: 2622-2629.
13. Robins, H. S., P. V. Campregher, S. K. Srivastava, A. Wacher, C. J. Turtle, O. Kahsai, S. R. Riddell, E. H. Warren, and C. S. Carlson. 2009. Comprehensive assessment of T-cell receptor b-chain diversity in ab T cells. Blood 114: 4099-4107.
14. Freeman, J. D., R. L. Warren, J. R. Webb, B. H. Nelson, and R. A. Holt. 2009. Profiling the T-cell receptor b-chain repertoire by massively parallel sequencing. Genome Res. 19: 1817-1824.
15. Mamedov, I. Z., O. V. Britanova, D. A. Bolotin, A. V. Chkalina, D. B. Staroverov, I. V. Zvyagin, A. A. Kotlobay, M. A. Turchaninova, D. A. Fedorenko, A. A. Novik, et al. 2011. Quantitative tracking of T cell clones after haematopoietic stem cell transplantation. EMBO Mol. Med. 3: 201-207.
16. Warren, R. L., J. D. Freeman, T. Zeng, G. Choe, S. Munro, R. Moore, J. R. Webb, and R. A. Holt. 2011. Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res. 21: 790-797.
17. Robins, H. S., S. K. Srivastava, P. V. Campregher, C. J. Turtle, J. Andriesen, S. R. Riddell, C. S. Carlson, and E. H. Warren. 2010. Overlap and effective size of the human CD8+ T cell receptor repertoire. Sci. Transl. Med. 2: 47ra64.
18. Quigley, M. F., H. Y. Greenaway, V. Venturi, R. Lindsay, K. M. Quinn, R. A. Seder, D. C. Douek, M. P. Davenport, and D. A. Price. 2010. Convergent recombination shapes the clonotypic landscape of the naive T-cell repertoire. Proc. Natl. Acad. Sci. USA 107: 19414-19419.
19. Li, H., C. Ye, G. Ji, X. Wu, Z. Xiang, Y. Li, Y. Cao, X. Liu, D. C. Douek, D. A. Price, and J. Han. 2012. Recombinatorial biases and convergent recombination determine interindividual TCRb sharing in murine thymocytes. J. Immunol. 189: 2404-2413.
20. Shugay, M., D. A. Bolotin, E. V. Putintseva, M. V. Pogorelyy, I. Z. Mamedov, and D. M. Chudakov. 2013. Huge overlap of individual TCR beta repertoires. Front. Immunol. 4: 466.
21. Putintseva, E. V., O. V. Britanova, D. B. Staroverov, E. M. Merzlyak, M. A. Turchaninova, M. Shugay, D. A. Bolotin, M. V. Pogorelyy, I. Z. Mamedov, V. Bobrynina, et al. 2013. Mother and child T cell receptor repertoires: deep profiling study. Front. Immunol. 4: 463.
22. Zvyagin, I. V., M. V. Pogorelyy, M. E. Ivanova, E. A. Komech, M. Shugay, D. A. Bolotin, A. A. Shelenkov, A. A. Kurnosov, D. B. Staroverov, D. M. Chudakov, et al. 2014. Distinctive properties of identical twins TCR repertoires revealed by high-Throughput sequencing. Proc. Natl. Acad. Sci. USA 111: 5980-5985.
23. Venturi, V., M. F. Quigley, H. Y. Greenaway, P. C. Ng, Z. S. Ende, T. McIntosh, T. E. Asher, J. R. Almeida, S. Levy, D. A. Price, et al. 2011. A mechanism for TCR sharing between T cell subsets and individuals revealed by pyrosequencing. J. Immunol. 186: 4285-4294.
24. Föhse, L., J. Suffner, K. Suhre, B. Wahl, C. Lindner, C. W. Lee, S. Schmitz, J. D. Haas, S. Lamprecht, C. Koenecke, et al. 2011. High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells. Eur. J. Immunol. 41: 3101-3113.
25. Estorninho, M., V. B. Gibson, D. Kronenberg-Versteeg, Y. F. Liu, C. Ni, K. Cerosaletti, and M. Peakman. 2013. A novel approach to tracking antigenexperienced CD4 T cells into functional compartments via tandem deep and shallow TCR clonotyping. J. Immunol. 191: 5430-5440.
26. Edholm, E. S., L. M. Albertorio Saez, A. L. Gill, S. R. Gill, L. Grayfer, N. Haynes, J. R. Myers, and J. Robert. 2013. Nonclassical MHC class Idependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians. Proc. Natl. Acad. Sci. USA 110: 14342-14347.
27. Greenaway, H. Y., B. Ng, D. A. Price, D. C. Douek, M. P. Davenport, and V. Venturi. 2013. NKT and MAIT invariant TCRa sequences can be produced efficiently by VJ gene recombination. Immunobiology 218: 213-224.
28. Lepore, M., A. Kalinichenko, A. Colone, B. Paleja, A. Singhal, A. Tschumi, B. Lee, M. Poidinger, F. Zolezzi, L. Quagliata, et al. 2014. Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRb repertoire. Nat. Commun. 5: 3866.
29. Linnemann, C., B. Heemskerk, P. Kvistborg, R. J. Kluin, D. A. Bolotin, X. Chen, K. Bresser, M. Nieuwland, R. Schotte, S. Michels, et al. 2013. High-Throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19: 1534-1541.
30. Gros, A., P. F. Robbins, X. Yao, Y. F. Li, S. Turcotte, E. Tran, J. R. Wunderlich, A. Mixon, S. Farid, M. E. Dudley, et al. 2014. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124: 2246-2259.
31. Zhu, J., T. Peng, C. Johnston, K. Phasouk, A. S. Kask, A. Klock, L. Jin, K. Diem, D. M. Koelle, A. Wald, et al. 2013. Immune surveillance by CD8aa+ skinresident T cells in human herpes virus infection. Nature 497: 494-497.
32. Ye, L., J. C. Goodall, L. Zhang, E. V. Putintseva, B. Lam, L. Jiang, W. Liu, J. Yin, L. Lin, T. Li, et al. 2016. TCR usage, gene expression and function of two distinct FOXP3+Treg subsets within CD4+CD25hi T cells identified by expression of CD39 and CD45RO. Immunol. Cell Biol. 94: 293-305.
33. Feng, Y., J. van der Veeken, M. Shugay, E. V. Putintseva, H. U. Osmanbeyoglu, S. Dikiy, B. E. Hoyos, B. Moltedo, S. Hemmers, P. Treuting, et al. 2015. A mechanism for expansion of regulatory T-cell repertoire and its role in selftolerance. Nature 528: 132-136.
34. Nguyen, P., J. Ma, D. Pei, C. Obert, C. Cheng, and T. L. Geiger. 2011. Identification of errors introduced during high throughput sequencing of the T cell receptor repertoire. BMC Genomics 12: 106.
35. Bolotin, D. A., I. Z. Mamedov, O. V. Britanova, I. V. Zvyagin, D. Shagin, S. V. Ustyugova, M. A. Turchaninova, S. Lukyanov, Y. B. Lebedev, and D. M. Chudakov. 2012. Next generation sequencing for TCR repertoire profiling: platform-specific features and correction algorithms. Eur. J. Immunol. 42: 3073-3083.
36. Baum, P. D., V. Venturi, and D. A. Price. 2012. Wrestling with the repertoire: The promise and perils of next generation sequencing for antigen receptors. Eur. J. Immunol. 42: 2834-2839.
37. Bolotin, D. A., M. Shugay, I. Z. Mamedov, E. V. Putintseva, M. A. Turchaninova, I. V. Zvyagin, O. V. Britanova, and D. M. Chudakov. 2013. MiTCR: software for T-cell receptor sequencing data analysis. Nat. Methods 10: 813-814.
38. Mamedov, I. Z., O. V. Britanova, I. V. Zvyagin, M. A. Turchaninova, D. A. Bolotin, E. V. Putintseva, Y. B. Lebedev, and D. M. Chudakov. 2013. Preparing unbiased T-cell receptor and antibody cDNA libraries for the deep next generation sequencing profiling. Front. Immunol. 4: 456.
39. Shugay, M., O. V. Britanova, E. M. Merzlyak, M. A. Turchaninova, I. Z. Mamedov, T. R. Tuganbaev, D. A. Bolotin, D. B. Staroverov, E. V. Putintseva, K. Plevova, et al. 2014. Towards error-free profiling of immune repertoires. Nat. Methods 11: 653-655.
40. Venturi, V., D. A. Price, D. C. Douek, and M. P. Davenport. 2008. The molecular basis for public T-cell responses? Nat. Rev. Immunol. 8: 231-238.
41. Shugay, M., S. Lukyanov, and D. M. Chudakov. 2015. Sequencing rare T-cell populations. Oncotarget 6: 39393-39394.
42. Shugay, M., D. V. Bagaev, M. A. Turchaninova, D. A. Bolotin, O. V. Britanova, E. V. Putintseva, M. V. Pogorelyy, V. I. Nazarov, I. V. Zvyagin, V. I. Kirgizova, et al. 2015. VDJtools: unifying post-Analysis of T cell receptor repertoires. PLOS Comput. Biol. 11: e1004503.
43. Kivioja, T., A. Vähärautio, K. Karlsson, M. Bonke, M. Enge, S. Linnarsson, and J. Taipale. 2011. Counting absolute numbers of molecules using unique molecular identifiers. Nat. Methods 9: 72-74.
44. Kinde, I., J. Wu, N. Papadopoulos, K. W. Kinzler, and B. Vogelstein. 2011. Detection and quantification of rare mutations with massively parallel sequencing. Proc. Natl. Acad. Sci. USA 108: 9530-9535.
45. Vollmers, C., R. V. Sit, J. A. Weinstein, C. L. Dekker, and S. R. Quake. 2013. Genetic measurement of memory B-cell recall using antibody repertoire sequencing. Proc. Natl. Acad. Sci. USA 110: 13463-13468.
46. Vander Heiden, J. A., G. Yaari, M. Uduman, J. N. Stern, K. C. OConnor, D. A. Hafler, F. Vigneault, and S. H. Kleinstein. 2014. pRESTO: A toolkit for processing high-Throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30: 1930-1932.
47. Egorov, E. S., E. M. Merzlyak, A. A. Shelenkov, O. V. Britanova, G. V. Sharonov, D. B. Staroverov, D. A. Bolotin, A. N. Davydov, E. Barsova, Y. B. Lebedev, et al. 2015. Quantitative profiling of immune repertoires for minor lymphocyte counts using unique molecular identifiers. J. Immunol. 194: 6155-6163.
48. Best, K., T. Oakes, J. M. Heather, J. Shawe-Taylor, and B. Chain. 2015. Computational analysis of stochastic heterogeneity in PCR amplification efficiency revealed by single molecule barcoding. Sci. Rep. 5: 14629.
49. Day, E. K., A. J. Carmichael, I. J.Ten Berge, E. C. Waller, J. G. Sissons, and M. R. Wills. 2007. Rapid CD8+ T cell repertoire focusing and selection of highaffinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J. Immunol. 179: 3203-3213.
50. Iancu, E. M., P. Corthesy, P. Baumgaertner, E. Devevre, V. Voelter, P. Romero, D. E. Speiser, and N. Rufer. 2009. Clonotype selection and composition of human CD8 T cells specific for persistent herpes viruses varies with differentiation but is stable over time. J. Immunol. 183: 319-331.
51. Maini, M. K., N. Gudgeon, L. R. Wedderburn, A. B. Rickinson, and P. C. Beverley. 2000. Clonal expansions in acute EBV infection are detectable in the CD8 and not the CD4 subset and persist with a variable CD45 phenotype. J. Immunol. 165: 5729-5737.
52. Weekes, M. P., M. R. Wills, J. G. Sissons, and A. J. Carmichael. 2004. Longterm stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations. J. Immunol. 173: 5843-5851.
53. Klarenbeek, P. L., E. B. Remmerswaal, I. J.Ten Berge, M. E. Doorenspleet, B. D. van Schaik, R. E. Esveldt, S. D. Koch, A.Ten Brinke, A. H. van Kampen, F. J. Bemelman, et al. 2012. Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years. PLoS Pathog. 8: e1002889.
54. Kedzierska, K., S. A. Valkenburg, P. C. Doherty, M. P. Davenport, and V. Venturi. 2012. Use it or lose it: establishment and persistence of T cell memory. Front. Immunol. 3: 357.
55. Carter, M. S., J. Doskow, P. Morris, S. Li, R. P. Nhim, S. Sandstedt, and M. F. Wilkinson. 1995. A regulatory mechanism that detects premature nonsense codons in T-cell receptor transcripts in vivo is reversed by protein synthesis inhibitors in vitro. J. Biol. Chem. 270: 28995-29003.
56. Wang, J., V. M. Vock, S. Li, O. R. Olivas, and M. F. Wilkinson. 2002. A quality control pathway that down-regulates aberrant T-cell receptor (TCR) transcripts by a mechanism requiring UPF2 and translation. J. Biol. Chem. 277: 18489-18493.
57. Bhalla, A. D., J. P. Gudikote, J. Wang, W. K. Chan, Y. F. Chang, O. R. Olivas, and M. F. Wilkinson. 2009. Nonsense codons trigger an RNA partitioning shift. J. Biol. Chem. 284: 4062-4072.
58. Gardner, L. B. 2008. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol. Cell. Biol. 28: 3729-3741.
59. Soothill, P. W., K. H. Nicolaides, C. H. Rodeck, and H. Gamsu. 1986. Blood gases and acid-base status of the human second-Trimester fetus. Obstet. Gynecol. 68: 173-176.
60. Bhuvanagiri, M., A. M. Schlitter, M. W. Hentze, and A. E. Kulozik. 2010. NMD: RNA biology meets human genetic medicine. Biochem. J. 430: 365-377.
61. Bruno, I. G., R. Karam, L. Huang, A. Bhardwaj, C. H. Lou, E. Y. Shum, H.W. Song, M. A. Corbett, W. D. Gifford, J. Gecz, et al. 2011. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol. Cell 42: 500-510.
62. Lykke-Andersen, S., and T. H. Jensen. 2015. Nonsense-mediated mRNA decay: An intricate machinery that shapes transcriptomes. Nat. Rev. Mol. Cell Biol. 16: 665-677.
63. Feeney, A. J. 1990. Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. J. Exp. Med. 172: 1377-1390.
64. Bogue, M., S. Gilfillan, C. Benoist, and D. Mathis. 1992. Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny. Proc. Natl. Acad. Sci. USA 89: 11011-11015.
65. George, J. F., Jr., and H. W. Schroeder, Jr. 1992. Developmental regulation of D beta reading frame and junctional diversity in T cell receptor-beta transcripts from human thymus. J. Immunol. 148: 1230-1239.
66. Cherrier, M., A. Cardona, I. Rosinski-Chupin, F. Rougeon, and N. Doyen. 2002. Substantial N diversity is generated in T cell receptor alpha genes at birth despite low levels of terminal deoxynucleotidyl transferase expression in mouse thymus. Eur. J. Immunol. 32: 3651-3656.
67. Elhanati, Y., A. Murugan, C. G. Callan, Jr., T. Mora, and A. M. Walczak. 2014. Quantifying selection in immune receptor repertoires. Proc. Natl. Acad. Sci. USA 111: 9875-9880.
68. Yan, J., J. M. Greer, R. Hull, J. D. OSullivan, R. D. Henderson, S. J. Read, and P. A. McCombe. 2010. The effect of ageing on human lymphocyte subsets: comparison of males and females. Immun. Ageing 7: 4. doi:10.1186/1742-4933-7-4
69. Venturi, V., H. Y. Chin, T. E. Asher, K. Ladell, P. Scheinberg, E. Bornstein, D. van Bockel, A. D. Kelleher, D. C. Douek, D. A. Price, and M. P. Davenport. 2008. TCR b-chain sharing in human CD8+ T cell responses to cytomegalovirus and EBV. J. Immunol. 181: 7853-7862.
70. Takada, K., and S. C. Jameson. 2009. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9: 823-832.
71. Takeda, S., H. R. Rodewald, H. Arakawa, H. Bluethmann, and T. Shimizu. 1996. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-Term life span. Immunity 5: 217-228.
72. Brocker, T. 1997. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J. Exp. Med. 186: 1223-1232.
73. Rudd, B. D., V. Venturi, G. Li, P. Samadder, J. M. Ertelt, S. S. Way, M. P. Davenport, and J. Nikolich-Zugich. 2011. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl. Acad. Sci. USA 108: 13694-13699.
74. Solana, R., R. Tarazona, A. E. Aiello, A. N. Akbar, V. Appay, M. Beswick, J. A. Bosch, C. Campos, S. Cantisan, L. Cicin-Sain, et al. 2012. CMV and immunosenescence: from basics to clinics. Immun. Ageing 9: 23.
75. Fulöp, T., A. Larbi, and G. Pawelec. 2013. Human T cell aging and the impact of persistent viral infections. Front. Immunol. 4: 271.
76. Jacobs, J. M., A. Cohen, E. Ein-Mor, and J. Stessman. 2014. Gender differences in survival in old age. Rejuvenation Res. 17: 499-506.
77. Clambey, E. T., L. F. van Dyk, J. W. Kappler, and P. Marrack. 2005. Nonmalignant clonal expansions of CD8+ memory T cells in aged individuals. Immunol. Rev. 205: 170-189.
78. Bradley, L. M., J. Harbertson, G. C. Freschi, R. Kondrack, and P. J. Linton. 2000. Regulation of development and function of memory CD4 subsets. Immunol. Res. 21: 149-158.
79. Dittel, B. N. 2008. CD4 T cells: balancing the coming and going of autoimmunemediated inflammation in the CNS. Brain Behav. Immun. 22: 421-430.
80. Cabaniols, J. P., N. Fazilleau, A. Casrouge, P. Kourilsky, and J. M. Kanellopoulos. 2001. Most ab T cell receptor diversity is due to terminal deoxynucleotidyl transferase. J. Exp. Med. 194: 1385-1390.
81. Zemlin, M., R. L. Schelonka, K. Bauer, and H. W. Schroeder, Jr. 2002. Regulation and chance in the ontogeny of B and T cell antigen receptor repertoires. Immunol. Res. 26: 265-278.
82. Pido-Lopez, J., N. Imami, and R. Aspinall. 2001. Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin. Exp. Immunol. 125: 409-413.
83. Olsson, J., A. Wikby, B. Johansson, S. Löfgren, B. O. Nilsson, and F. G. Ferguson. 2000. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: The Swedish longitudinal OCTO immune study. Mech. Ageing Dev. 121: 187-201.
84. Derhovanessian, E., A. B. Maier, K. Hähnel, H. Zelba, A. J. de Craen, H. Roelofs, E. P. Slagboom, R. G. Westendorp, and G. Pawelec. 2013. Lower proportion of naive peripheral CD8+ T cells and an unopposed pro-inflammatory response to human cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. Age (Dordr.) 35: 1387-1399.
85. Nathanson, C. A. 1984. Sex differences in mortality. Annu. Rev. Sociol. 10: 191-213.
86. Reade, M. C., S. Yende, G. DAngelo, L. Kong, J. A. Kellum, A. E. Barnato, E. B. Milbrandt, C. Dooley, F. B. Mayr, L. Weissfeld, and D. C. Angus, Genetic and Inflammatory Markers of Sepsis Investigators. 2009. Differences in immune response may explain lower survival among older men with pneumonia. Crit. Care Med. 37: 1655-1662.
87. Sansoni, P., R. Vescovini, F. F. Fagnoni, A. Akbar, R. Arens, Y. L. Chiu, L. Cicin-Sain, J. Dechanet-Merville, E. Derhovanessian, S. Ferrando-Martinez, et al. 2014. New advances in CMV and immunosenescence. Exp. Gerontol. 55: 54-62.
88. Wertheimer, A. M., M. S. Bennett, B. Park, J. L. Uhrlaub, C. Martinez, V. Pulko, N. L. Currier, D. Nikolich-Zugich, J. Kaye, and J. Nikolich-Zugich. 2014. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192: 2143-2155.
89. Tolstoy, L. 2014. Anna Karenina. Random House, London.
90. Mayer, A., V. Balasubramanian, T. Mora, and A. M. Walczak. 2015. How a welladapted immune system is organized. Proc. Natl Acad. Sci. USA 112: 5950-5955.
91. Arstila, T. P., A. Casrouge, V. Baron, J. Even, J. Kanellopoulos, and P. Kourilsky. 1999. A direct estimate of the human ab T cell receptor diversity. Science 286: 958-961.
92. Turchaninova, M. A., O. V. Britanova, D. A. Bolotin, M. Shugay, E. V. Putintseva, D. B. Staroverov, G. Sharonov, D. Shcherbo, I. V. Zvyagin, I. Z. Mamedov, et al. 2013. Pairing of T-cell receptor chains via emulsion PCR. Eur. J. Immunol. 43: 2507-2515.
93. Howie, B., A. M. Sherwood, A. D. Berkebile, J. Berka, R. O. Emerson, D. W. Williamson, I. Kirsch, M. Vignali, M. J. Rieder, C. S. Carlson, and H. S. Robins. 2015. High-Throughput pairing of T cell receptor a and b sequences. Sci. Transl. Med. 7: 301ra131.