Disruption of TNF-α/TNFR1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection

J Invest Dermatol. 2012 May;132(5):1425-34. doi: 10.1038/jid.2011.489. Epub 2012 Feb 9.

Abstract

One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFRs) that block TNF-α function. The response to VV skin infection under conditions of TNF-α deficiency, however, has not been reported. We found that TNFR1-/- mice developed larger primary lesions, numerous satellite lesions, and higher skin virus levels after VV scarification. Following their recovery, VV-scarified TNFR1-/- mice were fully protected against challenge with a lethal intranasal dose of VV, suggesting these mice had developed an effective memory immune response. A functional systemic immune response was further demonstrated by enhanced production of VV-specific IFN-γ and VV-specific CD8(+) T cells in spleens and draining lymph nodes. Interestingly, bone marrow (BM)-reconstitution studies using wild-type (WT) BM in TNFR1-/- host mice, but not TNFR1-/- BM in WT host mice, reproduced the original results seen in TNFR1-/- mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Our data suggest that lack of TNFR1 leads to a skin-specific immune deficiency, and that resident skin cells have a crucial role in mediating an optimal immune defense to VV cutaneous infection via TNF-α/TNFR1 signaling.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Viral / blood*
  • CD8-Positive T-Lymphocytes*
  • Immunity, Innate
  • Immunoglobulin G / blood
  • Interferon-gamma / metabolism
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / immunology*
  • Skin / immunology*
  • Skin / virology
  • Tumor Necrosis Factor-alpha / immunology*
  • Vaccinia / immunology*
  • Vaccinia / pathology
  • Vaccinia virus / immunology*
  • Viral Load

Substances

  • Antibodies, Viral
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma