Journal of Clinical Immunology

, Volume 33, Issue 1, pp 14–21 | Cite as

EVER2 Deficiency is Associated with Mild T-cell Abnormalities

  • Amandine Crequer
  • Capucine Picard
  • Vincent Pedergnana
  • Annick Lim
  • Shen-Ying Zhang
  • Laurent Abel
  • Slawomir Majewski
  • Jean-Laurent Casanova
  • Stefania Jablonska
  • Gerard Orth
  • Emmanuelle Jouanguy
Original Research


Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4+ and CD8+ T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4+ and effector memory CD8+ T cells, a bias of the TCR Vαβ and Vγδ repertoires and an increase of skin-homing CD4+ T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both.


Epidermodysplasia verruciformis EVER immune deficiencies T cells 



We thank the members of both branches of the Saint Giles Laboratory of Human Genetics of Infectious Diseases, but also Aminata Diabate, Corinne Jacques, Chantal Harre and Stephanie N’Daga for excellent technical assistance, and Svetlana Mazel for flow cytometry expertise. We warmly thank the patients for their participation. This work was supported by grants from INSERM, University Paris Descartes, the Rockefeller University, the St. Giles Foundation, and the Rockefeller University Center for Clinical and Translational Science grant number UL1RR024143.

Competing interest statement

The authors declare that they have no competing financial interests.

Supplementary material

10875_2012_9749_MOESM1_ESM.tif (1 mb)
High resolution image (TIFF 1.03 MB)
10875_2012_9749_MOESM2_ESM.tif (1014 kb)
High resolution image (TIFF 0.99 MB)


  1. 1.
    Orth G. Host defenses against human papillomaviruses: lessons from epidermodysplasia verruciformis. Curr Top Microbiol Immunol. 2008;321:59–83.PubMedCrossRefGoogle Scholar
  2. 2.
    Lutzner MA. Epidermodysplasia verruciformis. An autosomal recessive disease characterized by viral warts and skin cancer. A model for viral oncogenesis. Bull Cancer. 1978;65(2):169–82.PubMedGoogle Scholar
  3. 3.
    Orth G. Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Semin Immunol. 2006;18(6):362–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Prawer SE, Pass F, Vance JC, Greenberg LJ, Yunis EJ, Zelickson AS. Depressed immune function in epidermodysplasia verruciformis. Arch Dermatol. 1977;113(4):495–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Glinski W, Jablonska S, Langner A, Obalek S, Haftek M, Proniewska M. Cell-mediated immunity in epidermodysplasia verruciformis. Dermatologica. 1976;153(4):218–27.PubMedCrossRefGoogle Scholar
  6. 6.
    Glinski W, Obalek S, Jablonska S, Orth G. T cell defect in patients with epidermodysplasia verruciformis due to human papillomavirus type 3 and 5. Dermatologica. 1981;162(3):141–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Majewski S, Skopinska-Rozewska E, Jablonska S, Wasik M, Misiewicz J, Orth G. Partial defects of cell-mediated immunity in patients with epidermodysplasia verruciformis. J Am Acad Dermatol. 1986;15(5 Pt 1):966–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Pereira de Oliveira WR, Carrasco S, Neto CF, Rady P, Tyring SK. Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis. J Dermatol. 2003;30(3):203–9.PubMedGoogle Scholar
  9. 9.
    Majewski S, Malejczyk J, Jablonska S, Misiewicz J, Rudnicka L, Obalek S, et al. Natural cell-mediated cytotoxicity against various target cells in patients with epidermodysplasia verruciformis. J Am Acad Dermatol. 1990;22(3):423–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Kaminski M, Pawinska M, Jablonska S, Szmurlo A, Majewski S, Orth G. Increased natural killer cell activity in patients with epidermodysplasia verruciformis. Arch Dermatol. 1985;121(1):84–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002;32(4):579–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Casanova JL, Abel L. Primary immunodeficiencies: a field in its infancy. Science. 2007;317(5838):617–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Alcais A, Quintana-Murci L, Thaler DS, Schurr E, Abel L, Casanova JL. Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity? Ann N Y Acad Sci. 2010;1214:18–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Lazarczyk M, Pons C, Mendoza JA, Cassonnet P, Jacob Y, Favre M. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med. 2008;205(1):35–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Landini MM, Zavattaro E, Borgogna C, Azzimonti B, De Andrea M, Colombo E, et al. Lack of EVER2 protein in two epidermodysplasia verruciformis patients with skin cancer presenting previously unreported homozygous genetic deletions in the EVER2 gene. J Invest Dermatol. 2012;132(4):1305–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Keresztes G, Mutai H, Heller S. TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins. BMC Genomics. 2003;4(1):24.PubMedCrossRefGoogle Scholar
  17. 17.
    Haase H, Rink L. Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr. 2009;29:133–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Yu M, Lee WW, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M, Lamar DL, et al. Regulation of T cell receptor signaling by activation-induced zinc influx. J Exp Med. 2011;208(4):775–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Lazarczyk M, Dalard C, Hayder M, Dupre L, Pignolet B, Majewski S, et al. EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation. PLoS One. 2012;7(6):e39995.PubMedCrossRefGoogle Scholar
  20. 20.
    Crequer A, Troeger A, Patin E, Ma CS, Picard C, Pedergnagna V, et al. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest. 2012;In press.Google Scholar
  21. 21.
    Crequer A, Picard C, Patin E, D'Amico A, Abhyankar A, Munzer M, Debre M, de Saint-Basile G, Fischer A, Abel L, Orth G, Casanova J.-L., Jouanguy E. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. In revision Plos one. 2012;In press.Google Scholar
  22. 22.
    Jablonska S, Dabrowski J, Jakubowicz K. Epidermodysplasia verruciformis as a model in studies on the role of papovaviruses in oncogenesis. Cancer Res. 1972;32(3):583–9.PubMedGoogle Scholar
  23. 23.
    Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, et al. The vast majority of CLA + T cells are resident in normal skin. J Immunol. 2006;176(7):4431–9.PubMedGoogle Scholar
  24. 24.
    Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9(10):679–91.PubMedGoogle Scholar
  25. 25.
    Pauls K, Schon M, Kubitza RC, Homey B, Wiesenborn A, Lehmann P, et al. Role of integrin alphaE(CD103)beta7 for tissue-specific epidermal localization of CD8+ T lymphocytes. J Invest Dermatol. 2001;117(3):569–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Aochi S, Nakanishi G, Suzuki N, Setsu N, Suzuki D, Aya K, et al. A novel homozygous mutation of the EVER1/TMC6 gene in a Japanese patient with epidermodysplasia verruciformis. Br J Dermatol. 2007;157(6):1265–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P, et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T cells survival. Blood. 2011.Google Scholar
  28. 28.
    Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA, et al. The phenotype of human STK4 deficiency. Blood. 2012.Google Scholar
  29. 29.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Randall KL, Chan SS, Ma CS, Fung I, Mei Y, Yabas M, et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 2011;208(11):2305–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Soler D, Humphreys TL, Spinola SM, Campbell JJ. CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking. Blood. 2003;101(5):1677–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Amandine Crequer
    • 1
    • 4
  • Capucine Picard
    • 2
    • 3
    • 4
  • Vincent Pedergnana
    • 2
    • 4
  • Annick Lim
    • 5
  • Shen-Ying Zhang
    • 1
    • 2
  • Laurent Abel
    • 1
    • 2
    • 4
  • Slawomir Majewski
    • 6
  • Jean-Laurent Casanova
    • 1
    • 2
    • 4
    • 7
  • Stefania Jablonska
    • 8
  • Gerard Orth
    • 9
  • Emmanuelle Jouanguy
    • 1
    • 2
    • 4
  1. 1.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Human Genetics of Infectious Diseases, Necker BranchINSERM U980ParisFrance
  3. 3.Study Center of Primary ImmunodeficienciesNecker Hospital, AP-HPParisFrance
  4. 4.Paris Descartes UniversityParisFrance
  5. 5.Department of ImmunologyPasteur InstituteParisFrance
  6. 6.Department of Dermatology and VenereologyCenter of Diagnostics and Treatment of STD at Warsaw Medical UniversityWarsawPoland
  7. 7.Pediatric Immuno-hematology UnitNecker Hospital, AP-HPParisFrance
  8. 8.Department of DermatologyWarsaw School of MedecineWarsawPoland
  9. 9.Department of VirologyPasteur InstituteParisFrance

Personalised recommendations