Home LiteratureArticle Details
PMID: 23395677 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults.

Immunity ·Vol. 38 ·No. 2 ·2013-02-21 ·Pages 373-83

Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM

Abstract

Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%-90%, averaging over 50%) of CD4(+) T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments.

MeSH Terms
Adult Amino Acid Sequence CD4-Positive T-Lymphocytes/immunology,pathology Cell Proliferation Child Clone Cells HIV Infections/immunology,pathology,virology HIV-1/immunology Humans Immunologic Memory Immunophenotyping Infant, Newborn Influenza A Virus, H1N1 Subtype/immunology Influenza Vaccines/immunology Influenza, Human/immunology,pathology,prevention & control,virology Molecular Sequence Data Peptides/immunology Phenotype Receptors, Antigen, T-Cell/genetics,immunology T-Cell Antigen Receptor Specificity Vaccination
Chemicals
Influenza Vaccines Peptides Receptors, Antigen, T-Cell
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Su Laura F
Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94304, USA.
Kidd Brian A
Han Arnold
Kotzin Jonathan J
Davis Mark M
References (52)
52 references, click to expand
  1. Tetramer-guided epitope mapping: rapid identification and characterization of immunodominant CD4+ T cell epitopes from complex antigens.
    J Immunol. 2001 Jun 1;166(11):6665-70 PMID: 11359821
  2. Fine specificity and cross-clade reactivity of HIV type 1 Gag-specific CD4+ T cells.
    AIDS Res Hum Retroviruses. 2004 Mar;20(3):315-25 PMID: 15117455
  3. Finegoldia magna: a forgotten pathogen in prosthetic joint infection rediscovered by molecular biology.
    Clin Infect Dis. 2009 Oct 15;49(8):1244-7 PMID: 19757992
  4. The crystal structure of a T cell receptor in complex with peptide and MHC class II.
    Science. 1999 Dec 3;286(5446):1913-21 PMID: 10583947
  5. A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition.
    Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13279-84 PMID: 15331779
  6. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells.
    Nat Immunol. 2011 Jun;12(6):478-84 PMID: 21739670
  7. Heterologous immunity between viruses.
    Immunol Rev. 2010 May;235(1):244-66 PMID: 20536568
  8. HLA DR4w4-binding motifs illustrate the biochemical basis of degeneracy and specificity in peptide-DR interactions.
    J Immunol. 1993 Sep 15;151(6):3163-70 PMID: 7690794
  9. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau.
    Vaccine. 2005 Jan 19;23(9):1197-204 PMID: 15629363
  10. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies.
    Lancet. 2003 Jun 28;361(9376):2183-8 PMID: 12842371
  11. Structural basis of specificity and cross-reactivity in T cell receptors specific for cytochrome c-I-E(k).
    J Immunol. 2011 May 15;186(10):5823-32 PMID: 21490152
  12. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia.
    Immunity. 1998 Jun;8(6):683-91 PMID: 9655482
  13. CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory.
    Mech Ageing Dev. 1996 Mar 29;86(3):173-95 PMID: 8733112
  14. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health.
    J Clin Invest. 2004 Feb;113(3):451-63 PMID: 14755342
  15. Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma.
    Cancer Immun. 2009 Jun 05;9:5 PMID: 19496531
  16. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude.
    Immunity. 2007 Aug;27(2):203-13 PMID: 17707129
  17. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers.
    J Clin Invest. 2003 Sep;112(6):831-42 PMID: 12975468
  18. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions.
    Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13694-9 PMID: 21813761
  19. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States.
    N Engl J Med. 1995 Dec 28;333(26):1721-5 PMID: 7491134
  20. Epitope repertoire of human CD4+ T cells on tetanus toxin: identification of immunodominant sequence segments.
    J Infect Dis. 1997 Feb;175(2):382-91 PMID: 9203659
  21. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion.
    J Exp Med. 2009 Feb 16;206(2):435-48 PMID: 19188498
  22. Global epidemiology and control of Trichomonas vaginalis.
    Curr Opin Infect Dis. 2008 Feb;21(1):56-64 PMID: 18192787
  23. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.
    Nat Immunol. 2009 Feb;10(2):149-57 PMID: 19136960
  24. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial.
    BMJ. 2010 Nov 30;341:c6495 PMID: 21118875
  25. Phenotype and function of human T lymphocyte subsets: consensus and issues.
    Cytometry A. 2008 Nov;73(11):975-83 PMID: 18785267
  26. Direct ex vivo detection of HLA-DR3-restricted cytomegalovirus- and Mycobacterium tuberculosis-specific CD4+ T cells.
    Hum Immunol. 2005 Sep;66(9):950-61 PMID: 16360834
  27. CDR3 loop flexibility contributes to the degeneracy of TCR recognition.
    Nat Immunol. 2003 Mar;4(3):241-7 PMID: 12563259
  28. Derivation and maintenance of virtual memory CD8 T cells.
    J Immunol. 2012 Mar 15;188(6):2516-23 PMID: 22308307
  29. Diversity in T cell memory: an embarrassment of riches.
    Immunity. 2009 Dec 18;31(6):859-71 PMID: 20064446
  30. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis.
    Ann Rheum Dis. 2005 Aug;64(8):1199-204 PMID: 15640269
  31. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors.
    J Immunol. 2012 Feb 15;188(4):1933-41 PMID: 22246631
  32. Randomized trials to study the nonspecific effects of vaccines in children in low-income countries.
    Pediatr Infect Dis J. 2010 May;29(5):457-61 PMID: 20431383
  33. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen.
    Arthritis Rheum. 2005 Nov;52(11):3424-32 PMID: 16255019
  34. Universal influenza DNA vaccine encoding conserved CD4+ T cell epitopes protects against lethal viral challenge in HLA-DR transgenic mice.
    Vaccine. 2010 Jan 8;28(3):664-72 PMID: 19895924
  35. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.
    Immunity. 2012 Feb 24;36(2):288-97 PMID: 22365666
  36. Insulin as an autoantigen in NOD/human diabetes.
    Curr Opin Immunol. 2008 Feb;20(1):111-8 PMID: 18178393
  37. Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa.
    Int J Epidemiol. 1999 Dec;28(6):1088-95 PMID: 10661652
  38. High-affinity binding of short peptides to major histocompatibility complex class II molecules by anchor combinations.
    Proc Natl Acad Sci U S A. 1994 May 10;91(10):4456-60 PMID: 8183931
  39. Negative selection and peptide chemistry determine the size of naive foreign peptide-MHC class II-specific CD4+ T cell populations.
    J Immunol. 2010 Oct 15;185(8):4705-13 PMID: 20861357
  40. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?
    Nat Immunol. 2001 Sep;2(9):797-801 PMID: 11526389
  41. Human T-cell clones recognize chemically synthesized peptides of influenza haemagglutinin.
    Nature. 1982 Nov 4;300(5887):66-9 PMID: 6982419
  42. Expression and kinetics of cytokines determined by intracellular staining using flow cytometry.
    J Immunol Methods. 1999 Feb 1;223(1):115-21 PMID: 10037239
  43. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis.
    Immunity. 2010 Feb 26;32(2):214-26 PMID: 20137986
  44. Inborn errors of immunity to infection: the rule rather than the exception.
    J Exp Med. 2005 Jul 18;202(2):197-201 PMID: 16027233
  45. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation.
    Nat Rev Immunol. 2012 Mar 16;12(4):306-15 PMID: 22421787
  46. Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens.
    J Immunother. 2003 Jul-Aug;26(4):349-56 PMID: 12843797
  47. Several common HLA-DR types share largely overlapping peptide binding repertoires.
    J Immunol. 1998 Apr 1;160(7):3363-73 PMID: 9531296
  48. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire.
    J Immunol. 2012 Mar 15;188(6):2537-44 PMID: 22327072
  49. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire.
    Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3874-9 PMID: 15001705
  50. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa.
    BMJ. 2000 Dec 9;321(7274):1435-8 PMID: 11110734
  51. High-throughput gene expression profiling of memory differentiation in primary human T cells.
    BMC Immunol. 2008 Aug 01;9:44 PMID: 18673556
  52. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection.
    Immunity. 2008 Jun;28(6):859-69 PMID: 18499487
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2012.10.021
Published
2013-02-21
Epub
2013-00-07
Pages
373-83
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3626102
Subset
IM
Grants
NIAMS NIH HHS · K08 AR059760 · United States
NIDDK NIH HHS · T32 DK007056 · United States
NIAID NIH HHS · U19 AI057229 · United States
NIAID NIH HHS · U19 AI090019 · United States
NIAID NIH HHS · U19AI090019 · United States
Howard Hughes Medical Institute · United States
NIDDK NIH HHS · 5 T32 DK007056-36 · United States
Corrections
CommentIn
PMID: 23435321
CommentIn
PMID: 23438820
External Links
PubMed source DOI: 10.1016/j.immuni.2012.10.021 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2