Initiation of adaptive immune responses by transcutaneous immunization

106

102

There are conflicting data in the literature regarding the role of epidermal Langerhans cells (LC) in promoting skin immune responses. On one hand, LC can be extremely potent APCs in vitro, and are thought to be involved in contact hypersensitivity (CHS). On the other hand, it seems counterintuitive that a cell type continually exposed to pathogens at the organism’s barrier surfaces should readily trigger potent T cell responses. Indeed, LC depletion in one model led to enhanced contact hypersensitivity, suggesting they play a negative regulatory role. However, apparently similar LC depletion models did not show enhanced CHS, and in one case showed reduced CHS. In this study we found that acute depletion of mouse LC reduced CHS, but the timing of toxin administration was critical: toxin administration 3 days before priming did not impair CHS, whereas toxin administration 1 day before priming did. We also show that LC elimination reduced the T cell response to epicutaneous immunization with OVA protein Ag. However, this reduction was only observed when OVA was applied on the flank skin, and not on the ear. Additionally, peptide immunization was not blocked by depletion, regardless of the site. Finally we show that conditions which eliminate epidermal LC but spare other Langerin+ DC do not impair the epicutaneous immunization response to OVA. Overall, our results reconcile previous conflicting data in the literature, and suggest that Langerin+ cells do promote T cell responses to skin Ags, but only under defined conditions.

Section: A Limited Immune-promoting Role For Langerin ϩ Cellsmentioning

confidence: 99%

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Wang

Bursch

Kissenpfennig

et al. 2008

106

102

“…Immunization strategies through the skin have proven to be feasible and elicit both systemic and mucosal immunity (4,5). In murine studies, CD4 ϩ and CD8 ϩ T cell responses were both observed after peptide immunization through the skin (6,7).…”

Section: Accination With Dendritic Cells (Dc)mentioning

confidence: 99%

Tumor Immunotherapy by Epicutaneous Immunization Requires Langerhans Cells

Stoitzner

Green

Jung

et al. 2008

103

A role for Langerhans cells (LC) in the induction of immune responses in the skin has yet to be conclusively demonstrated. We used skin immunization with OVA protein to induce immune responses against OVA-expressing melanoma cells. Mice injected with OVA-specific CD8+ T cells and immunized with OVA onto barrier-disrupted skin had increased numbers of CD8+ T cells in the blood that produced IFN-γ and killed target cells. These mice generated accelerated cytotoxic responses after secondary immunization with OVA. Prophylactic or therapeutic immunization with OVA onto barrier-disrupted skin inhibited the growth of B16.OVA tumors. LC played a critical role in the immunization process because depletion of LC at the time of skin immunization dramatically reduced the tumor-protective effect. The topically applied Ag was presented by skin-derived LC in draining lymph nodes to CD8+ T cells. Thus, targeting of tumor Ags to LC in vivo is an effective strategy for tumor immunotherapy.

“…Understanding how human DCs respond to innate immune stimuli and the effect that this has on the adaptive immune response is important in generating vaccine adjuvants that can more efficiently induce an appropriate response. The study of human skin DCs may be particularly important due to the interest surrounding transcutaneous vaccination strategies (19).…”

Section: Cd34mentioning

confidence: 99%

TLR-Stimulated CD34 Stem Cell-Derived Human Skin-Like and Monocyte-Derived Dendritic Cells Fail to Induce Th17 Polarization of Naive T Cells but Do Stimulate Th1 and Th17 Memory Responses

Duraisingham

Hornig

Gotch

et al. 2009

Dendritic cells (DCs) are important in linking innate and adaptive immune responses by priming and polarizing naive CD4+ Th cells, but little is known about the effect of different human DC subsets on Th cells, particularly Th17 cells. We have investigated the ability of TLR-stimulated human Langerhans cells (LC), dermal DCs (dDC), and monocyte-derived DCs (moDC) to affect naive and memory Th17 and Th1 responses. MoDCs stimulated greater memory T cell proliferation while LCs and dDCs more potently stimulated naive T cell proliferation, indicating functionally distinct subsets of DCs. TLR stimulation of all three DC types was unable to induce Th17 polarization from naive T cell precursors, despite inducing Th1 polarization. Dectin stimulation of DCs in IMDM was however able to produce Th17 cells. TLR-stimulated DCs were capable of inducing IL-17A and IFN-γ production from memory T cells, although the mechanism used by each DC subset differed. MoDCs partially mediated this effect on memory Th1 and Th17 cells by the production of soluble factors, which correlated with their ability to secrete IL-12p70 and IL-23. In contrast, LCs and dDCs were able to elicit a similar memory response to moDCs, but in a contact dependent manner. Additionally, the influence of microbial stimulation was demonstrated with TLR3 and TLR7/8 agonists inducing a Th1 response, whereas TLR2 or dectin stimulation of moDCs enhanced the IL-17 response. This study emphasizes the differences between human DC subsets and demonstrates that both the DC subset and the microbial stimulus influence the Th cell response.