Acute Ablation of Langerhans Cells Enhances Skin Immune Responses

Bobr, Aleh; Olvera-Gómez, Irlanda; Igyártó, Botond Z.; Haley, Krystal; Hogquist, Kristin A.; Kaplan, Daniel H.

doi:10.4049/jimmunol.1001802

Cited by 122 publications

(115 citation statements)

References 30 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…The reason for this augmented reactivity is unclear, but it may be due to failing peripheral tolerance mechanisms in the absence of LC throughout life (1,11,32). More recently, aggravated CHS was also reported following acute LC ablation (33). How to reconcile the incongruent results obtained with the different inducible LCdepletion models remains elusive.…”

mentioning

confidence: 51%

“…The reason for enhanced reactivity observed thus far only in human Langerin bacterial artificial chromosome transgenic mice with constitutive or acute ablation of LC remains enigmatic (31,33), in particular, because CHS responses were unaffected in Batf3-deficient mice specifically lacking Langerin + CD103 + dermal DC (15). In these mice, CHS should have been attenuated if LC had a regulatory function, as has been suggested (31,33). In a mouse model independent of diphtheria toxin-mediated cell ablation, we demonstrated that CHS responses are reduced (and not enhanced) in the selective absence of LC (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Conditional Deletion of TGF-βR1 Using Langerin-Cre Mice Results in Langerhans Cell Deficiency and Reduced Contact Hypersensitivity

Zahner

Kel

Martina

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

The critical role of Langerhans cells (LC) in contact hypersensitivity (CHS) was recently questioned in studies using different LC-depletion mouse models. On one hand, inducible ablation of LC led to diminished ear swelling, suggesting functional redundancy between LC and (Langerin+) dermal dendritic cells (DC). On the other hand, constitutive or acute depletion of LC resulted in an enhanced reaction, supporting a regulatory role of LC in CHS. To address this controversy by conditional gene targeting, we generated Langerin-Cre knockin mice. Breeding these mice to a Cre-reporter strain demonstrated robust and specific DNA recombination in LC, as well as other Langerin+ tissue DC. In agreement with the vital requirement of TGF-β signaling for LC development, crossing Langerin-Cre to mice homozygous for a loxP-flanked TGF-βR1 allele resulted in permanent LC deficiency, whereas the homeostasis of dermal Langerin+ DC was unaffected. In the absence of LC, induction of CHS in these Langerin+ DC-specific TGF-βR1–deficient mice elicited decreased ear swelling compared with controls. This novel approach provided further evidence against a regulatory function of LC in CHS. Moreover, these Langerin-Cre mice represent a unique and powerful tool to dissect the role and molecular control of Langerin+ DC populations beyond LC.

show abstract

mentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of TGF-βR1 Using Langerin-Cre Mice Results in Langerhans Cell Deficiency and Reduced Contact Hypersensitivity

Zahner

Kel

Martina

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…As we have seen with other huLangerin transgenic mice, transgene expression was specific for LCs (13,16,17). In the dermis of YFP mice, only migratory LCs as defined by expression of muLangerin in the absence of CD103 expressed huLangerin (Fig.…”

Section: Resultsmentioning

confidence: 84%

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Bobr

Igyártó

Haley

et al. 2012

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

Self Cite

103

101

View full text Add to dashboard Cite

Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-β1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-β1 is complicated by the requirement of TGF-β1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-β1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER T2 mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER T2 × TGF-βRII fl and huLangerin-CreER T2 × TGF-β1 fl mice. Excision of the TGFβRII or TGFβ1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-β1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammationinduced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.skin immunology | pSMAD2/3 | tolerance

show abstract

“…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: 99%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

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

151

135

View full text Add to dashboard Cite

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...

show abstract

Acute Ablation of Langerhans Cells Enhances Skin Immune Responses

Cited by 122 publications

References 30 publications

Conditional Deletion of TGF-βR1 Using Langerin-Cre Mice Results in Langerhans Cell Deficiency and Reduced Contact Hypersensitivity

Conditional Deletion of TGF-βR1 Using Langerin-Cre Mice Results in Langerhans Cell Deficiency and Reduced Contact Hypersensitivity

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Langerhans cells are precommitted to immune tolerance induction

Contact Info

Product

Resources

About