Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross‐tolerance

EMBO Molecular Medicine

Vincent Flacher²  Christoph H Tripp²  David G Mairhofer²  Ralph M Steinman¹  Patrizia Stoitzner²  Juliana Idoyaga¹ 

[1] Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA;Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria

关键词: CD8+ T‐cell responses;    dendritic cells;    Langerhans cells;    skin;    tolerance;   

DOI  :  10.15252/emmm.201303283

来源: Wiley

【 摘 要 】

Abstract

Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8⁺ T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin⁺ dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin⁺ dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8⁺ T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8⁺ T cells. Langerin/OVA combined with imiquimod could not prime CD8⁺ T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin⁺ dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8⁺ T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.

Synopsis

The properties of two murine skin antigen-presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA-immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

• Both Langerin⁺ dermal DCs and epidermal Langerhans cells (LC) can present exogenous antigen to CD8⁺ T cells.
• Langerin⁺ dermal DCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8⁺ T-cell priming.
• Specific adjuvants can be used to independently harness the different potential of distinct DC subsets simultaneously targeted by an antigen.
• Treatment of skin with imiquimod, an agonist of TLR7, does not result in potent immune responses when the antigen is targeted to Langerin, thereby relativizing the paradigm stating that mature DCs always promote immunity.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.