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Cited by 95T-cell and B-cell ImmunologyCervical Cancer and HPV ResearchImmunotherapy and Immune Responses

Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy

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Béziat, Vivien, Rapaport, Franck, Hu, Jiafen, Titeux, Matthias, Bonnet des Claustres, Mathilde, Bourgey, Mathieu, Griffin, Heather, Bandet, Élise +66 more·2021·Cell
DOI 10.1016/j.cell.2021.06.004PMC PMC8329841
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Abstract

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

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  • A recent study in patients with CD28 deficiency strongly suggests that the poor antibody responses seen in those patients after vaccination result from a deficiency of CD4 T cell response, due to the absence of CD28 co-stimulation signaling.

    “A recent study in patients with CD28 de ciency strongly suggest that the poor antibody responses seen in those patients after vaccination results from a de ciency of CD4 T cell response, due to the absence of CD28 co-stimulation signaling (16).”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [16]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • ISG15, an interferon-inducible protein necessary for viral protection in mice, does not have the same critical role in humans.

    “Similarly, ISG15, an interferon-inducible protein necessary for viral protection in mice, does not have the same critical role in humans(48-50).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [48]

    The supplied Results passage concerns CD28 splice variants, and the Methods passages concern viral assays, not ISG15. Searches of our copy for ISG15 and for the claimed mouse–human difference found no passage addressing ISG15’s role in viral protection. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Alcohol intake alters the secretion of adipokines including leptin and adiponectin by adipose tissue, activating both KCs and HSCs, resulting in accelerated liver inflammation and fibrosis, respectively.

    “Alcohol intake alters the secretion of adipokines including leptin and adiponectin by adipose tissue, activating both KCs and HSCs, resulting in accelerated liver inflammation and fibrosis, respectively (47, 48).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [48]

    The Results sections on CD28-dependent T-cell responses and leukocyte subsets (page unavailable) discuss inherited CD28 deficiency, not alcohol-related liver disease. Searches for alcohol, leptin, adiponectin, Kupffer cells, and hepatic stellate cells found no passage in our copy addressing the claimed pathway. (LLM, conf=0.78)

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Authors
Béziat, V., Rapaport, F., Hu, J., Titeux, M., Bonnet des Claustres, M., Bourgey, M., Griffin, H., Bandet, É., Ma, C. S., Sherkat, R., Rokni-Zadeh, H., Louis, D. M., Changi-Ashtiani, M., Delmonte, O. M., Fukushima, T., Habib, T., Guennoun, A., Khan, T., Bender, N., Rahman, M., About, F., Yang, R., Rao, G., Rouzaud, C., Li, J., Shearer, D., Balogh, K., Al Ali, F., Ata, M., Dabiri, S., Momenilandi, M., Nammour, J., Alyanakian, M.-A., Leruez-Ville, M., Guenat, D., Materna, M., Marcot, L., Vladikine, N., Soret, C., Vahidnezhad, H., Youssefian, L., Saeidian, A. H., Uitto, J., Catherinot, É., Navabi, S. S., Zarhrate, M., Woodley, D. T., Jeljeli, M., Abraham, T., Belkaya, S., Lorenzo, L., Rosain, J., Bayat, M., Lanternier, F., Lortholary, O., Zakavi, F., Gros, P., Orth, G., Abel, L., Prétet, J.-L., Fraitag, S., Jouanguy, E., Davis, M. M., Tangye, S. G., Notarangelo, L. D., Marr, N., Waterboer, T., Langlais, D., Doorbar, J., Hovnanian, A., Christensen, N., Bossuyt, X., Shahrooei, M., & Casanova, J.-L.
Affiliations
  • Inserm (FR)
  • Rockefeller University (US)
  • Pennsylvania State University (US)
  • McGill University (CA)
  • University of Cambridge (GB)
  • Garvan Institute of Medical Research (AU)
  • Isfahan University of Medical Sciences (IR)
  • Stanford Medicine (US)
  • National Institutes of Health (US)
  • Tokyo Institute of Technology (JP)
  • German Cancer Research Center (DE)
  • Hôpital Necker-Enfants Malades (FR)
  • Zahedan University of Medical Sciences (IR)
  • KU Leuven (BE)
  • Centre Hospitalier Universitaire de Besançon (FR)
  • Thomas Jefferson University (US)
  • Hôpital Foch (FR)
  • University of Southern California (US)
  • Hôpital Cochin (FR)
  • Ahvaz Jundishapur University of Medical Sciences (IR)
  • Institut Pasteur (FR)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Béziat, Vivien
  • Casanova, Jean-Laurent
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-07
Volume
184
Issue
14
Pages
3812-3828.e30
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.06.004
PMC
PMC8329841
OpenAlex
W3174150961
Cited by
95
References
3
Citations by year
2026: 14 · 2025: 11 · 2024: 19 · 2023: 17 · 2022: 23 · 2021: 10
FWCI
6.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ScholarSphere (Penn State Libraries) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • Lirias (submittedVersion)
Funders
  • Cancer Research UK (28754)
  • Agence Nationale de la Recherche (ANR-10-IAHU-0001, ANR-11-LABX-0021, ANR-13-PDOC-0025)
  • National Institutes of Health (UL1TR001866)
  • Medical Research Council (MR/S024409/1, MC_PC_13050)
  • Japan Society for the Promotion of Science (21H00276)
  • National Institute of Allergy and Infectious Diseases (R01AI143810, U19AI057229)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
T cell costimulation, human papillomavirus, HPV 2, keratinocytes, T cell immunity
MeSH terms
Adult, Amino Acid Sequence, Animals, Base Sequence, Child, Female, Genes, Recessive, Homozygote, Humans, Immunologic Memory, Male, Mice, Inbred C57BL, Oncogenes, Papilloma, Pedigree, Endopeptidases, RNA, Messenger, Skin, T-Lymphocytes, CD4-Positive T-Lymphocytes, Keratinocytes, CD28 Antigens, Jurkat Cells, Protein Sorting Signals, Papillomaviridae, Inheritance Patterns, Mice, Immunity, Humoral, HEK293 Cells

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