The Journal of Allergy and Clinical Immunology
Volume 123, Issue 4 , Pages 875-882.e1 , April 2009

Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization

  • Haoli Jin, MD, PhD

      Affiliations

    • Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
    • These authors contributed equally to this work.
  • ,
  • Lalit Kumar, PhD

      Affiliations

    • Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
    • These authors contributed equally to this work.
  • ,
  • Clinton Mathias, PhD

      Affiliations

    • Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
  • ,
  • David Zurakowski, PhD

      Affiliations

    • Department of Anesthesia and Surgery, Children's Hospital, Boston, Mass
  • ,
  • Hans Oettgen, MD, PhD

      Affiliations

    • Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
  • ,
  • Leonid Gorelik, PhD

      Affiliations

    • Biogen Idec, Inc, Cambridge, Mass
  • ,
  • Raif Geha, MD

      Affiliations

    • Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
    • Corresponding Author InformationReprint requests: Raif Geha, MD, Division of Immunology, Room 10210, Karp Family Research Building, Children's Hospital, One Blackfan Circle, Boston, MA 02115.

Received 20 August 2008 ,Revised 22 January 2009 ,Accepted 4 February 2009.

  • Image Result

    TLR2 mRNA expression after skin tape stripping and painting with OX. Quantitative PCR analysis of TLR2 mRNA expression in mouse skin after tape stripping (n = 5; A) or application of 2% OX in ethanol

    TLR2 mRNA expression after skin tape stripping and painting with OX. Quantitative PCR analysis of TLR2 mRNA expression in mouse skin after tape stripping (n = 5; A) or application of 2% OX in ethanol to shaved skin (n = 4; B) is shown. Results were normalized for glyceraldehyde-3-phosphate dehydrogenase expression and expressed as fold induction compared with time 0. Values are presented as the mean ± SD. P < .05.

  • Image Result
    Impaired epidermal thickening and IFN-γ mRNA expression but normal cellular infiltration and TH2 cytokine production in OVA-sensitized skin of TLR2−/− mice. A, Representative skin histology (original

    Impaired epidermal thickening and IFN-γ mRNA expression but normal cellular infiltration and TH2 cytokine production in OVA-sensitized skin of TLR2−/− mice. A, Representative skin histology (original magnification ×200). B, Skin-infiltrating CD4+ T cells and eosinophils. C, Quantitative PCR analysis of mRNA levels of IL-4, IL-15, and IL-13 and IFN-γ. n = 6-7. P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, Saline; KO, knockout.

  • Image Result
    Impaired TH1 systemic response to epicutaneous sensitization with OVA in TLR2−/− mice. A, Cytokine secretion by splenocytes in response to OVA stimulation in vitro. B, Serum levels of OVA-specific imm

    Impaired TH1 systemic response to epicutaneous sensitization with OVA in TLR2−/− mice. A, Cytokine secretion by splenocytes in response to OVA stimulation in vitro. B, Serum levels of OVA-specific immunoglobulin isotypes. n = 6-7. P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, Saline; KO, knockout.

  • Image Result
    Impaired contact hypersensitivity in TLR2−/− mice. A, Ear swelling in sensitized mice challenged with OX hapten. Results represent the difference in thickness between hapten- and vehicle-challenged ea

    Impaired contact hypersensitivity in TLR2−/− mice. A, Ear swelling in sensitized mice challenged with OX hapten. Results represent the difference in thickness between hapten- and vehicle-challenged ears (n = 10). B, Representative ear skin histology at 24 hours after challenge (original magnification ×200). C and D, IL-4 (Fig 4, C) and IFN-γ (Fig 4, D) mRNA expression as fold induction in hapten-challenged over vehicle-challenged ears. P < .05, ∗∗P < .01, and ∗∗∗P < .0001. KO, Knockout.

  • Image Result
    Impaired OX-specific IgG2a response in TLR2−/− mice. Serum anti-OX IgG1 and IgG2a levels in mice sensitized and challenged with OX. Serum was taken 24 hours after the challenge. ∗P < .05, ∗∗P < .01, a

    Impaired OX-specific IgG2a response in TLR2−/− mice. Serum anti-OX IgG1 and IgG2a levels in mice sensitized and challenged with OX. Serum was taken 24 hours after the challenge. P < .05, ∗∗P < .01, and ∗∗∗P < .001. KO, Knockout.

  • Image Result
    Impaired capacity of TLR2−/− DCs to drive a TH1 response. Proliferation (A) and secretion of IL-4 (B), IL-13 (C), and IFN-γ (D) by CD4+ OTII T cells stimulated with OVA323-339 peptide in the presence

    Impaired capacity of TLR2−/− DCs to drive a TH1 response. Proliferation (A) and secretion of IL-4 (B), IL-13 (C), and IFN-γ (D) by CD4+ OTII T cells stimulated with OVA323-339 peptide in the presence of CD11c+ splenic DCs derived from WT and TLR2−/− mice. Data are representative of 3 experiments. P < .05 and ∗∗P < .01. 3H-Td, Tritiated thymidine; KO, knockout.

  • Image Result
    CCL17/thymus and activation-regulated (TARC) chemokine (A) and CCL11/eotaxin-1 (B) mRNA expression in OVA-sensitized skin of TLR2−/− mice (n = 5-6). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, saline;

    CCL17/thymus and activation-regulated (TARC) chemokine (A) and CCL11/eotaxin-1 (B) mRNA expression in OVA-sensitized skin of TLR2−/− mice (n = 5-6). P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, saline; KO, knockout.

 Supported by the Atopic Dermatitis and Vaccinia Immunization Network; National Institutes of Health/National Institute of Allergy and Infectious Diseases contract NO1 (AI 40030); and a US Public Health Service grant AR-047417 to R.G. H.J. has received a postdoctoral fellowship from the American Heart Association.

 Disclosure of potential conflict of interest: H. Jin has received research support from the American Heart Association. H. Oettgen has served as a consultant and scientific advisor for Schering-Plough and as a consultant for Genentech and has received research support from Novartis. L. Gorelik is employed by Biogen Idec, Inc. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(09)00233-4

doi: 10.1016/j.jaci.2009.02.007

The Journal of Allergy and Clinical Immunology
Volume 123, Issue 4 , Pages 875-882.e1 , April 2009