Epidermal Langerhans Cells Are Dispensable for Humoral and Cell-Mediated Immunity Elicited by Gene Gun Immunization

Stoecklinger, Angelika; Grieshuber, Ines; Scheiblhofer, Sandra; Weiss, Richard; Ritter, Uwe; Kissenpfennig, Adrien; Malissen, Bernard; Romani, Nikolaus; Koch, Franz; Ferreira, Fátima; Thalhamer, Josef; Hammerl, Peter

doi:10.4049/jimmunol.179.2.886

Cited by 57 publications

(58 citation statements)

References 46 publications

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“…4). In unmanipulated mice in which the ratio of mLCs to m-DDCs in cLN is 1:3 rather than 1:1, the effect of LCs would be smaller, which may explain the lack of effect in some (9,33,34), but not all (7,8,35), models of contact sensitivity. The ability of LCs to suppress the response to antigen presentation by other DC subsets argues against the possibility that tolerance in our models is a default response to presentation of free antigen without active involvement of migrated skin DCs.…”

Section: Discussionmentioning

confidence: 98%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

150

135

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Antigen-dependent interactions between T lymphocytes and dendritic cells (DCs) can produce two distinct outcomes: tolerance and immunity. It is generally considered that all DC subsets are capable of supporting both tolerogenic and immunogenic responses, depending on their exposure to activating signals. Here, we tested whether epidermal Langerhans cells (LCs) can support immunogenic responses in vivo in the absence of antigen presentation by other DC subsets. CD4 T cells responding to antigen presentation by activated LCs initially proliferated but then failed to differentiate into effector/memory cells or to survive long term. The tolerogenic function of LCs was maintained after exposure to potent adjuvants and occurred despite up-regulation of the costimulatory molecules CD80, CD86, and IL-12, but was consistent with their failure to translocate the NF-κB family member RelB from the cytoplasm to the nucleus. Commitment of LCs to tolerogenic function may explain why commensal microorganisms expressing Toll-like receptor (TLR) ligands but confined to the skin epithelium are tolerated, whereas invading pathogens that breach the epithelial basement membrane and activate dermal DCs stimulate a strong immune response.D endritic cells (DCs) initiate adaptive immune responses by priming antigen-specific T cells in secondary lymphoid organs. After sampling antigens in peripheral tissues, DCs migrate to lymph nodes (LN), where they present antigenic peptides bound to major histocompatibility (MHC) molecules (1). Epidermal Langerhans cells (LCs) have long been regarded as prototypic DCs, highly active in antigen uptake and rapidly acquiring potent costimulatory capacity after in vitro culture (2). Recently, the immunogenicity of LCs has been questioned on the basis of findings in several in vivo experimental models. During herpes viral infection of the skin, migrated LCs isolated from draining LN (dLN) were unable to induce proliferation of virusspecific CD8 T cells in vitro (3). In LC ablation models, positive (4, 5), negative (6-8), and redundant (9) contributions of LCs to contact hypersensitivity responses were reported. The current lack of consensus regarding LC function may relate, at least in part, to the difficulties in determining the contribution of a relatively small number of LCs to responses driven primarily by non-LC DC subsets in cutaneous LN (cLN).Here we directly tested the in vivo function of LCs, using a previously described bone marrow (BM) chimeric mouse model in which only LCs can present specific antigen to CD4 T cells (10). In this model, all DC subsets express MHC class II IA molecules but only LCs express MHC class II IE, which is absolutely required to present moth cytochrome C peptide (pMCC) to 5C.C7 T-cell receptor (TCR) transgenic T cells (11,12). The response of adoptively transferred 5C.C7 CD4 T cells can thus be used as a readout for LC function. We compared 5C.C7 T-cell responses to LCs with those in chimeras expressing IE on nonepidermal DCs or all DC subsets, immunizing with peptide o...

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Section: Discussionmentioning

confidence: 98%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

150

135

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“…In contrast, LC were shown not to play a role in gene gun immunization on the abdominal skin (32). However, in gene gun immunization, the DNA is likely to penetrate deeper in the tissue than with epicutaneous immunization, and in this manner may target distinct APC.…”

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

confidence: 89%

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Wang

Bursch

Kissenpfennig

et al. 2008

The Journal of Immunology

Self Cite

106

102

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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.

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“…LC have also been reported to be dispensable for humoral and cellular responses initiated by gene gun immunization (23), but these studies were carried out and interpreted before the existence of langerin ϩ dDC was known. In retrospect, the protocol used in prior gene gun immunization studies involved weekly immunizations and repeated treatments of langerin-DTR mice with DT (23), and it is difficult to interpret the results. We sought to better define the function of LC and langerin ϩ dDC in the context of a response to a strong antigen (␤-galactosidase) delivered once into skin via gene gun immunization.…”

Section: Discussionmentioning

confidence: 99%

Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions

Nagao

Ginhoux

Leitner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

203

216

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A new langerin ؉ DC subset has recently been identified in murine dermis (langerin ؉ dDC), but the lineage and functional relationships between these cells and langerin ؉ epidermal Langerhans cells (LC) are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC allowed viable LC to be easily distinguished from langerin ؉ dDC in skin and lymphoid tissue and ex vivo as well. Differential expression of EpCAM and langerin revealed the presence of at least 3 distinct skin DC subsets. We determined that LC and langerin ؉ dDC exhibit different migratory capabilities in vitro and repopulate distinct anatomic compartments in skin at different rates after conditional depletion in vivo. Langerin ؉ dDC, in contrast to LC, did not require TGF␤1 for development. Carefully timed gene gun immunization studies designed to take advantage of the distinct repopulation kinetics of langerin ؉ dDC and LC revealed that langerin ؉ dDC were required for optimal production of ␤-galactosidase-specific IgG2a/c and IgG2b in the acute phase. In contrast, immunization via LC-deficient skin resulted in persistent and strikingly reduced IgG1 and enhanced IgG2a Ab production. Our data support the concepts that LC and langerin ؉ dDC represent distinct DC subsets that have specialized functions and that LC are important immunoregulatory cells. The presence of at least 3 functionally distinct skin DC subsets may have particular relevance for vaccines that are administered epicutaneously.EpCAM ͉ gene gun ͉ langerin ͉ TGF-beta T he remarkable phenotypic heterogeneity of DC, both between and within certain tissues, has been long recognized. To date, however, it has been possible to clearly relate DC phenotype to DC function in only a few instances, even in mice. For example, plasmacytoid DC are recognized as the primary source of virus-induced type I IFN (1), CD8␣ ϩ lymph node DC are largely responsible for cross-presentation of cell-associated antigen to CD8 T cells (2-4), and 33D1-reactive (DCIR2 ϩ ) splenic DC (as compared with CD205 ϩ DC) preferentially stimulate CD4 T cells (5). Epidermal Langerhans cells (LC) represent perhaps the most striking example of an extensively studied tissue DC subpopulation whose function is incompletely understood.LC have long been thought to play pivotal roles in initiating immunity by acquiring antigens that are encountered in skin, migrating to draining LN after activation, and stimulating antigen-specific T cells (6). However, recent studies suggested that LC do not function as essential antigen-presenting cells for anti-viral immune responses (2, 7) or for contact hypersensitivity reactions (8-12) in established murine models. Studies of LC have been challenging, in part, because readily detectable cell surface proteins that are constitutively expressed by epidermal LC and LC that have emigrated from epidermis have not been well recognized. The C-type lectin langerin has been regarded as a pathognomonic LC marker, but recent studies suggest that this protein is present in at le...

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Epidermal Langerhans Cells Are Dispensable for Humoral and Cell-Mediated Immunity Elicited by Gene Gun Immunization

Cited by 57 publications

References 46 publications

Langerhans cells are precommitted to immune tolerance induction

Langerhans cells are precommitted to immune tolerance induction

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions

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