Download PDF
Geburtshilfe Frauenheilkd 2000; 60(9): 464-468
DOI: 10.1055/s-2000-8019
Original Article

Georg Thieme Verlag Stuttgart · New York

Expansion of the CD8 + CD45RA + CD27 - CD28 - T-Cell Subset in Patients with HPV-Associated Cervical Cancer and its Precursors

Anstieg der CD8 + CD45RA + CD27 - CD 28 - T-Zell-Subpopulation bei Patientinnen mit HPV-assoziiertem Zervixkarzinom und seinen VorstufenH. Pilch1 , S. Günzel1 , C. Freitag2 , U. Schäffer1 , B. Tanner1 , P. G. Knapstein1 , M. Maeurer2
  • 1 Department of Obstetrics and Gynecology, Medical Center, University of Mainz, Germany
  • 2 Institute of Medical Microbiology, Medical Center, University of Mainz, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Also available at
    Permissions and Reprints

Summary

Objective

More than 90 % of cervical cancers and precursors are caused by infection with high-risk human papillomavirus (HPV). Cellular immune responses associated with HPV may be detectable in peripheral blood. The purpose of the present study was to assess the immune status in patients with HPV-infection and to identify T cell subsets which may serve as a surrogate marker for immune activation induced bei HPV.

Methods

Subsets of peripheral blood lymphocytes in women (n = 30) without signs of HPV-infection were compared with those of patients with histologically verified HPV-associated cervical intraepithelial neoplasia (CIN) (n = 22) or invasive cervical carcinomas (n = 16) using four-color flow cytometric analysis.

Results

One of the major changes in the T cell repertoire was a significant expansion of T cells characterized by the CD8+ CD45RA+ CD27- CD28- immune phenotype in patients with HPV associated CIN and cancer compared with the control group (p < 0.01 and 0.0001, respectively). This immune phenotype also differed significantly (p < 0.04) between patients with CIN and CC.

Conclusion

The significant T cell response in patients with HPV associated CIN and cancer suggests a proliferative expansion of HPV-antigen-experienced cytotoxic T cells. Further studies are necessary to determine the viral specificity and the validity of lymphocyte subset analysis for monitoring immune function in patients with HPV-associated neoplasia.

Zusammenfassung

Fragestellung

Die Beurteilung des Immunstatus bzw. eines Krankheitsprogresses bei Patienten mit chronischen Virusinfektionen ist oftmals durch die Untersuchung des peripheren Blutes möglich. Mehr als 90 % aller Dysplasien und Neoplasien der Zervix werden durch eine Infektion mit den humanen Papillomaviren vom High-risk-Typ verursacht, welche möglicherweise mit einer spezifischen zellulären Immunantwort verbunden ist. Das Ziel dieser Untersuchung war die Beurteilung des Immunstatus bei HPV-positiven Patientinnen und die Identifizierung eines bestimmten T-Zell-Repertoires, das möglicherweise als Surrogatmarker für eine HPV-spezifische zelluläre Immunaktivierung dienen könnte.

Material und Methodik

Die Subpopulation der peripheren Blutlymphozyten (PBL) von 30 Patientinnen (n = 30) ohne Zeichen einer HPV-Infektion wurden mit denen von Patientinnen mit histologisch gesicherter zervikaler intraepithelialer Neoplasie (CIN) (n = 22) und invasivem Zervixkarzinom (CC) (n = 16) mittels 4-Farben-Durchflusszytometrie verglichen.

Ergebnisse

Als eine signifikante Veränderung im T-Zell-Repertoire fand sich ein Anstieg der CD8 + CD45RA + CD27 - CD28 - T-Zell-Subpopulation bei Patientinnen mit HPV-assoziierter CIN und CC im Vergleich zur Kontrollgruppe (p < 0,01 resp. 0,0001). Selbst zwischen Patienten mit CIN und CC ließ sich ein signifikanter Unterschied in dieser T-Zell-Subpopulation objektivieren (p < 0,04).

Schlussfolgerung

Unsere Untersuchungen zeigen eine signifikante T-Zell-Antwort bei Patientinnen mit HPV-assoziierter Dysplasie bzw. Neoplasie der Cervix uteri in Form einer Proliferation von (HPV) antigen-erfahrenen zytotoxischen T-Lymphozyten-Analysen für das klinische Immunmonitoring bei Patienten mit HPV-assoziierter zervikaler Neoplasie zu belegen.

References

  • 1 Autran B, Carcelain G, Li T S, Blanc C, Mathez D, Tubiana R, Katlana C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4 + T cell homeostasis and function in advanced HIV disease.  Science. 1997;  277 112
    CrossrefPubMedGoogle Scholar
  • 2 Azuma A, Phillips J H, Lanier L. CD28-lymphocytes. Antigenic and functional properties.  J Immunol. 1993;  150 1147
    PubMedGoogle Scholar
  • 3 Borthwick N A, Bofill M, Gombert W M, Akbar A N, Medina E, Sagawa K, Lip M C, Johnson M A, Janossy G. Lymphocyte activation in HIV-I-infection. II. Functional defects of CD28 - T cells.  AIDS. 1994;  8 4312
    PubMedGoogle Scholar
  • 4 Callan M F, Tan L, Annels N, Og G S, Wilson J D, O'Callaghan C, Steven N, McMichael A J, Rickinson A B. Direct visualization of antigen-specific CD8 + T cells during the primary immune response to Epstein-Barr virus in vivo.  J Exp Med. 1998;  187 (9) 1395
    CrossrefPubMedGoogle Scholar
  • 5 Couedel-Courteille A, Le Grand R, Tulliez M, Guillet J G. Direct ex vivo simian immunodeficiency virus (SIV)-specific cytotoxic activity detected from small intestine intraepithelial lymphocytes of SIV-infected macawues at an advanced stage of infection.  J Virol. 1997;  71 1052
    PubMedGoogle Scholar
  • 6 Dutra W O, Martins-Filho O A, Cancado J R, Pinto-Diss J C, Brenner Z, Gazzinelli G, Carvalhi J F, Colloy D G. Chagasic patients lack CD28 expression on many of their circulation T lymphocytes.  Scand J Immunol. 1996;  43 88
    CrossrefPubMedGoogle Scholar
  • 7 Dutton R W, Bradlex L M, Swain S L. T cell memory.  Annu Rev Immunol. 1998;  16 201
    CrossrefPubMedGoogle Scholar
  • 8 Effros R B, Allsopp R, Chiu C P, Hausner M A, Hirji K, Wang L, Harley C B, Villeponteau B, West M D, Giorgi J V. Shortened telomers in the expanded CD28 - CD8 + cell subset in HIV disease implicate replicatice senecence in HIV pathogenesis.  AIDS. 1996;  10 17
    PubMedGoogle Scholar
  • 9 Fitzgerald J E, Ricalton N S, Meyer A C, West S G, Kaplan H, Behrendt C, Kotzin B L. Analysis of clonal CD8 + T cell expansion in normal individuals and patients with rheumatoid arthritis.  J Immunol. 1995;  154 3538
    PubMedGoogle Scholar
  • 10 Fragoni F F, Vescovini R, Mazzola M, Gologna B, Nigro E, Lavagetto G, Passeri M, Sansoni P. Expansion of cytotoxic CD8 + CD28 - T cells in healthy ageing people, including centenarians.  Immunology. 1996;  88 501
    CrossrefPubMedGoogle Scholar
  • 11 Garin L, Rigal D, Xouillet G, Nemoz C, Bernaud J, Merieux Y, Philippe N. Allogenic BMT in children: differential lymphocyte subset reconstitution according to the occurrence of acute GVHD.  Immunol Immunopathol. 1995;  77 139
    PubMedGoogle Scholar
  • 12 Hamann D, Baars P A, Rep M HG, Hooibring B, Garde K, Klein M R, Van Lier R AW. Phenotype and functional separation of memory and effector human CD8 + T cells.  J Exp Med. 1997;  186 1407
    CrossrefPubMedGoogle Scholar
  • 13 Kaneko H, Saito K, Hashimoto H, Yagita H, Okamura K, Azuma M. Preferential elimination of CD28 + T cells in systemic lupus erythematosus (SLE) and the relation with activation-induced apoptosis.  Clin Exp Immunol. 1996;  106 238
    PubMedGoogle Scholar
  • 14 Kuroda M J, Schmitz J E, Barouch D H, Craiu A, Allen T M, Sette A, Watkins D I, Forman M A, Letvin N L. Analysis of Gag-specific cytotoxic T lymphocytes in simian immunodeficiency virus-infected rhesus monkeys by cell staining with a tetrameric major histocompatibility complex class L-peptide complex.  J Exp Med. 1998;  187 (9) 1373
    CrossrefPubMedGoogle Scholar
  • 15 Latthe M, Tery L, MacDonald T T. High frequency of CD8 α homodimer-bearing T cells in human fetal intestine.  Eur J Immunol. 1994;  24 1703
    PubMedGoogle Scholar
  • 16 Lens S MA, Tesselaar K, van Oers M HJ, van Lier René A W. Control of lymphocyte function though CD27-CD70 interactions.  Immunol. 1998;  10 491
    PubMedGoogle Scholar
  • 17 Lynne J E, Schmid I, Matud J L, Hirji K, Buessow S, Shilian D M, Giorgi J V. Major expansion of select CD8 + subsets in acute Epstein-Barr virus infection: comparison with chronic human immunodeficiency virus disease.  J Infect Dis. 1998;  177 1083
    PubMedGoogle Scholar
  • 18 Mackall C L, Hakin F T, Gress R E. Restoration of T cell homeostasis after T cell depletion.  Sem Immunol. 1997;  9 339
    CrossrefPubMedGoogle Scholar
  • 19 Merkenschlager M, Beverly P C. Evidence for differential expression of CD45 isoforms by precursors for memory-dependent and independent cytotoxic response: human CD8 memory CTLp selectively express CD45RO (UCHL 1).  Int Immunol. 1989;  1 450
    PubMedGoogle Scholar
  • 20 Mollett L, Sadat-Sowti B, Duntze J, Leblond V, Bergeron F, Calvez V, Katlama P, Autran B. CD8+ CD57+ T lymphocytes are enriched in antigen-specific T cells capable of downmodulating cytotoxic activity.  Int Immunol. 1998;  10 311
    CrossrefPubMedGoogle Scholar
  • 21 Montagna D, Arico M, Montini E, De Benedetti F, Maccarlo R. Identification of HLA-unrestricted CD8 + /CD28 - cytotoxic T-cell clones specific for leukemic blasts in children with acute leukemia.  Cancer Res. 1995;  55 3835
    PubMedGoogle Scholar
  • 22 Monteiro J, Batliwalla F, Ostrer H, Gregersen P K. Shortened telomeres in clonally espanded CD28 - CD8 + counterparts.  J Immunol. 1996;  156 3587
    PubMedGoogle Scholar
  • 23 Monteiro J, Batliwalla F, Ostrer H, Gregersen P K. Shortened telomere in clonally expanded CD28 - CD8 + T cells imply a replicative history that is distinct from their CD28 + CD8 + counterparts.  J Immunol. 1996;  156 3587
    PubMedGoogle Scholar
  • 24 Murali-Krishna K, Altman J D, Suresh M, Sourdive D JD, Zajac A J, Miller J D, Slansky J, Ahmed R. Counting antigen-specific CD8 + cells: a reevaluation of bystander activation during viral infection.  Immunity. 1998;  8 (2) 177
    CrossrefPubMedGoogle Scholar
  • 25 Nociari M M, Telford W, Russo C. Postthymic development of CD-CD8 + T cell subset: age-associated expansion and shift from memory to naive phenotype.  J Immunol. 1999;  15 3327
    PubMedGoogle Scholar
  • 26 Ohteki T, MacDonald H R. Expression of the CD28 costimulatory molecule on subsets of murine intestinal intraepithelial lymphocytes correlates with lineage and responsiveness.  Eur J Immunol. 1993;  23 1251
    PubMedGoogle Scholar
  • 27 Okumura M, Fujii Y, Takeuchi Y, Inada K, Nakahara K, Hatsuda H. Age-related accumulations of LFA-1 high cells in a CD8+ CD45RAh T cell population.  Eur J Immunol. 1993;  23 1057
    PubMedGoogle Scholar
  • 28 Posnett D N, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy” [Published erratum appears in 1994; J Exp Med 179: 1077].  J Exp Med. 1994;  179 609
    CrossrefPubMedGoogle Scholar
  • 29 Roederer M, DeRosa S C, Watanabe N, Herzenberg L A. Dynamics of fine T-cell subsets during disease and after thymic ablation by mediastinal irradiation.  Sem Immunol. 1997;  9 389
    CrossrefPubMedGoogle Scholar
  • 30 Rosenberg Y J, Janossy G. The importance of lymphocyte trafficking in regulating blood lymphocyte levels during HIV and SIV infections.  Immunology. 1999;  11 (Vol) 139
    PubMedGoogle Scholar
  • 31 Rosenberg Y J, Cafaro A, Brennan T, Greenhouse J G, McKinnon K, Bellah S, Yalley-Ogunro J, Gartner S, Lewis M G. Characteristics of the CD8 + lymphocytosis during primary simian immunodeficiency virus infection.  AIDS. 1997;  11 959
    CrossrefPubMedGoogle Scholar
  • 32 Schwab R, Szabo P, Manavalan J S, Weksler M E, Posnett D N, Pannetier C, Kouribaky P, Even J. Expanded CD4 + and CD8 + T cell clones in elderly humans.  J Immunol. 1997;  158 4493
    PubMedGoogle Scholar
  • 33 Sperling A I, Bluestone J A. The complexities of T-cell co-stimulation: CD28 and beyond.  Immunol Rev. 1996;  153 155
    PubMedGoogle Scholar
  • 34 Vanham G, Kestens L, Penne G, Goilav C, Gigase P, Colebunders R, Vandenbruaene M, Goertian J, van der Groen G, Ceoppens J L. Subset markers of CD8 + cells and their relation to enhanced cytotoxic T-cell activity during human immunodeficiency virus infection.  J Clin Immunol. 1991;  11 345
    CrossrefPubMedGoogle Scholar
  • 35 Vingerhoets H H, Vanham G L, Kestens L L, Penne G G, Colebundem R L, Vandenbruaene M J, Goeman J, Gigase P L, De Boer M, Ceuppen J L. Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8 + cells from HIV-infected subjects.  Clin Exp Immunol. 1995;  100 425
    PubMedGoogle Scholar
  • 36 Wang E C, Lehner P J, Graham S, Borysiewicz I K. CD8 high (CD57 +) T cells in normal, healthy individuals specifically suppress the generation of cytotoxic T lymphocytes to Epstein-Barr virus-transformed B cell lines.  Eur J Immunol. 1994;  24 2903
    PubMedGoogle Scholar
  • 37 Westermann J, Ronneberg S, Joachim Fritz F, Pabst R. Proliferation of lymphocyte subsets in the adult rat: a comparison of different lymphoid organs.  Eur J Immunol. 1989;  19 1087
    PubMedGoogle Scholar
  • 38 Westermann J, Pabst R. Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system?.  Immunol Today. 1990;  11 406
    CrossrefPubMedGoogle Scholar
  • 39 Wills M R, Carmichael A J, Weekes M P, Mynard K, Okecha G, Hicks R, Sissons J GP. Human virus-specific CD8 + CTL clones revert from CD45ROhigh to CD45RAhigh in vivo: CD45RAhigh CD8 + T cells comprise both naive and memory cells.  J Immunol. 1999;  7080
    PubMedGoogle Scholar
  • 40 zur Hausen H. Papillomavirus in human cancers.  Molecular Carcinogen. 1988;  1 147
    PubMedGoogle Scholar
  • 41 zur Hausen H. Papillomaviruses as carcinomaviruses. Klein, G . Advances in Viral Oncology. Tumorigenic DNA Viruses. Vol. 8. New York; Raven Press 1989
    Google Scholar

M. D. Henryk Pilch

Department of OB/Gyn Mainz Medical Center University of Mainz

Langenbeckstraße 1

55101 Mainz

Germany