2. Academic Validation
  3. CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae

CD28-deficient mice are vulnerable to mouse papillomavirus MmuPV1 infection of the skin and mucosae

  • PLoS Pathog. 2026 Mar 10;22(3):e1013968. doi: 10.1371/journal.ppat.1013968.
Sarah Brendle 1 2,  Jingwei Li 1 2,  Song Lu 2,  Todd D Schell 3,  Michael Kozak 1 2,  Vonn Walter 4 5,  Debra Shearer 1 2,  Joshua Place 6,  Karla Balogh 1 2,  Jean-Laurent Casanova 7 8 9 10 11,  Neil Christensen 1 2 3,  Adam D Burgener 12 13 14,  Thomas T Murooka 15,  Yusheng Zhu 2,  Vivien Béziat 7 8 9 10,  Jiafen Hu 1 2
Affiliations

Affiliations

  • 1 Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
  • 2 Department of Pathology and Laboratory Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
  • 3 Department of Cell & Biological Systems, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
  • 4 Department of Public Health Sciences, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
  • 5 Department of Molecular and Precision Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
  • 6 Department of Comparative Medicine, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, United States of America.
  • 7 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.
  • 8 Imagine Institute, Paris-Cité University, Paris, France.
  • 9 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America.
  • 10 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 11 Howard Hughes Medical Institute, New York, New York, United States of America.
  • 12 Center for Global Health and Diseases, Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
  • 13 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Manitoba, Winnipeg, Canada.
  • 14 Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 15 Department of Immunology, University of Manitoba, Manitoba, Winnipeg, Canada.
PMID: 41805718 DOI: 10.1371/journal.ppat.1013968
Abstract

CD28 is a co-stimulatory molecule expressed on the surface of T cells. To date, three individuals with germline CD28 deficiency have been reported to develop recalcitrant, HPV-driven warts: one exhibited persistent lesions, another experienced disease resolution, and the third developed a chronic "tree-man" phenotype. In mice, we confirmed that CD28-knockout (CD28ko) Animals on the C57BL/6 (B6) background are susceptible to cutaneous Infection with mouse papillomavirus (MmuPV1); however, their skin warts regressed spontaneously approximately five weeks post-infection. Furthermore, we demonstrate that CD28ko mice are vulnerable to MmuPV1 Infection at HPV-relevant mucosal sites, including the most HPV prevalent sites: anogenital tract and oral cavity. Virions recovered from vaginal lavage were infectious but could be neutralized by the neutralizing monoclonal antibody MPV.A4. Viral clearance at mucosal sites was delayed in CD28ko mice, persisting for up to six weeks in the lower genital tract. Blocking the CD28 ligands CD80 and CD86 in B6 mice reproduced the CD28ko phenotype following MmuPV1 Infection and markedly reduced CD28 expression, implicating the CD28-CD80/CD86 axis in delayed viral clearance. Infected CD28ko mice showed a reduction in both CD4+ and CD8+ T cell population in the spleen compared to infected B6 mice, but an increase in CD11c+/F4-80+ cells, particularly the plasmacytoid dendritic cell (pDCs, SiglecH⁺) subset. Additionally, CD28ko mice exhibited delayed recruitment of activated CD4+ T cells to infected tissues. Accumulation of MmuPV1 E6/90-99-specific, tetramer-positive CD8+ cytotoxic T lymphocytes (CTLs) was slower in CD28ko than in B6 mice; these CTLs remained FoxP3 negative but displayed reduced efficacy in both in vitro killing and Antiviral cytokine assays. Adoptive transfer of CTLs from either B6 or CD28ko mice into MmuPV1-infected Rag1ko mice induced viral clearance at mucosal (oral) sites, whereas B6-derived CTLs achieved more complete regression of cutaneous (tail) lesions. Collectively, these findings indicate that CD28 deficiency delays but does not prevent the clearance of papillomavirus infections at both cutaneous and mucosal sites in mice.

Figures
Products
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    Product Name
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  • HY-D0938
    98.23%, Cell Proliferation Fluorescent Probe