Langerhans cells are precommitted to immune tolerance induction

Abstract

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...

Adaptive immunity to murine skin commensals

“…In skin, a similar balance may exist between antigen recognition and tolerance. Epidermal Langerhans cells may induce T-cell tolerance due to inefficient presentation of antigens from skin flora, whereas dermal DCs are stimulatory (3,22). Thus, commensals restricted to the surface of the skin may maintain tolerance, whereas bacteria penetrating the epithelial basement membrane to the dermis may induce an immune response.…”

“…The adaptive immune system, in contrast, has received less attention regarding its contribution to barrier function of the skin. Although tolerance would seem less necessary than for the more permeable gut, there is some evidence for tolerance (3); excess T-cell reactions are implicated in several common skin diseases, including atopic dermatitis and psoriasis.…”

The speed of change: towards a discontinuity theory of immunity?

“…It is however important to mention that there are other mechanisms at work in tolerance, and that acute antigenic challenges might also be tolerogenic 58 . Nevertheless, this principle leads to several original and testable predictions.…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…Gut and gut-associated lymphoid tissues also contain CD11b + CD103 + cells (Bogunovic et al, 2009;Varol et al, 2009). These migratory DC subsets also have quite unique functions (Kaplan et al, 2005;Bedoui et al, 2009;King et al, 2010;Lewis et al, 2011;Shklovskaya et al, 2011). DCs represent a rare type of leukocyte in lymphoid tissues.…”