Virus-encoded ectopic CD74 enhances poxvirus vaccine efficacy

Immunology. 2014 Apr;141(4):531-9. doi: 10.1111/imm.12210.

Abstract

Vaccinia virus (VV) has been used globally as a vaccine to eradicate smallpox. Widespread use of this viral vaccine has been tempered in recent years because of its immuno-evasive properties, with restrictions prohibiting VV inoculation of individuals with immune deficiencies or atopic skin diseases. VV infection is known to perturb several pathways for immune recognition including MHC class II (MHCII) and CD1d-restricted antigen presentation. MHCII and CD1d molecules associate with a conserved intracellular chaperone, CD74, also known as invariant chain. Upon VV infection, cellular CD74 levels are significantly reduced in antigen-presenting cells, consistent with the observed destabilization of MHCII molecules. In the current study, the ability of sustained CD74 expression to overcome VV-induced suppression of antigen presentation was investigated. Viral inhibition of MHCII antigen presentation could be partially ameliorated by ectopic expression of CD74 or by infection of cells with a recombinant VV encoding murine CD74 (mCD74-VV). In contrast, virus-induced disruptions in CD1d-mediated antigen presentation persisted even with sustained CD74 expression. Mice immunized with the recombinant mCD74-VV displayed greater protection during VV challenge and more robust anti-VV antibody responses. Together, these observations suggest that recombinant VV vaccines encoding CD74 may be useful tools to improve CD4⁺ T-cell responses to viral and tumour antigens.

Keywords: CD74; MHC; class II; invariant chain; virus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Viral / blood
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigen-Presenting Cells / virology
  • Antigens, CD1d / immunology
  • Antigens, CD1d / metabolism
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / immunology*
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Antigens, Viral / immunology
  • Antigens, Viral / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Smallpox Vaccine / administration & dosage
  • Smallpox Vaccine / genetics
  • Smallpox Vaccine / immunology*
  • Smallpox Vaccine / metabolism
  • Time Factors
  • Transfection
  • Vaccination
  • Vaccines, Synthetic / immunology
  • Vaccinia / immunology
  • Vaccinia / metabolism
  • Vaccinia / prevention & control*
  • Vaccinia / virology
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology*
  • Vaccinia virus / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / immunology*

Substances

  • Antibodies, Viral
  • Antigens, CD1d
  • Antigens, Differentiation, B-Lymphocyte
  • Antigens, Viral
  • CD1d antigen, mouse
  • Histocompatibility Antigens Class II
  • Smallpox Vaccine
  • Vaccines, Synthetic
  • Viral Proteins
  • invariant chain