Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis

Hum Immunol. 2012 Aug;73(8):844-51. doi: 10.1016/j.humimm.2012.04.008. Epub 2012 Apr 23.


HSV-1 persistently infects almost 90% of our population; however, only 30% of the infected subjects suffer from recurrent herpes lesions, most frequently herpes labialis (HL). We hypothesized that variations in toll-like receptor (TLR) functions might contribute to HL susceptibility. In our study, the TLR-2/1,-3, and -7/8 responses of immune cell subsets derived from asymptomatic HSV-1 carriers were compared with responses of subjects with HL history. Remarkably, natural killer (NK) cells isolated from HL subjects showed significantly lower IFN-γ responses selectively to the TLR3 agonist poly(I:C). Furthermore, the TLR3 L412F genetic polymorphism was found to reduce NK cell TLR3-responsiveness and is associated with susceptibility to recurrent HL. The TLR3 response detected in HL total peripheral blood mononuclear cells (PBMCs), however, was not impaired, indicating restoration of NK cell TLR3-deficiency through co-stimulatory functions. In conclusion, our results suggest that decreased TLR3 response of NK cells is associated with HL susceptibility; and potentially explain why symptomatic outbreak of HL usually occurs after stress or prolonged UV light exposure, when host co-stimulatory functions are disturbed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • Disease Susceptibility
  • Herpes Labialis / genetics*
  • Herpes Labialis / immunology
  • Herpes Labialis / virology
  • Herpesvirus 1, Human / immunology*
  • Herpesvirus 1, Human / pathogenicity
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / virology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / virology
  • Lymphocyte Activation / drug effects
  • Poly I-C / pharmacology
  • Polymorphism, Single Nucleotide
  • Recurrence
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / immunology


  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Interferon-gamma
  • Poly I-C