Langerhans cells (LC) are epidermal resident antigen-presenting cells that share a common ontogeny with macrophages but function as dendritic cells (DC). DC to activating stimuli allowed for highly efficient activation of naive T cells in mixed lymphocyte reactions. Inflammatory stimuli also greatly enhanced migration of LC out of Mouse monoclonal to CD4/CD8 (FITC/PE) the epidermis and into regional lymph nodes (LN). Thus, LC were considered the prototypical migratory DC envisioned by the DC-paradigm leading also to coinage of the term LC paradigm7. A corollary to the DC-paradigm is that presentation of self antigen by DC or LC in the absence of inflammatory stimuli deletes or silences autoreactive T cell clones thereby providing a basis for peripheral self-tolerance8. The location of LC at a barrier surface provides them with access to skin pathogens, commensal organisms, allergens, contact sensitizers and epidermal self-antigens. Thus, LC were assumed to mediate initiation of adaptive immunity against foreign antigens and tolerance to self-antigens found in the skin. More recently, there has been considerable progress investigating skin DC. Notably, several subsets of dermal DC were identified and have been shown to be required for many of the functions originally ascribed to LC. The phenotypes (Table 1) and functions of skin APC subsets have been reviewed recently9. In addition, SGI-1776 ic50 LC were found to be closely related to macrophages based on a shared ontogeny10,11. Thus, LC are turning out to be a rather unique cell type. This review will explore the unique aspects of murine LC biology and the contribution these cells provide to the establishment and regulation of cutaneous immune responses. Table 1. Mouse antigen-presenting phenotypes cultures of hematopoietic stem cell (HSC) precursors yield LC in the presence of TGF-1. Mice lacking the transcription factors ID2, Runx3, and Pu.1 as well as Axl that are all involved with TGF1-responses, lack or have reduced LC numbers14,15,27,28. BMP7, a member of the TGF- superfamily, is required for optimal LC development29. Finally, mice lack LC30. Interestingly, TGF-1 signaling is also required to maintain the LC network after it has developed. When mice in which in the TGF- pathway are conditionally ablated from LC they lose the capacity to remain in the epidermis and spontaneously migrate into regional lymph nodes31C33. Similarly, ablation of from differentiated LC results in spontaneous homeostatic LC migration32,34. Thus, despite many sources of TGF-1 in the epidermis (e.g. keratinocytes, T cells and LC), LC depend on autocrine and/or paracrine TGF-1 for epidermal residence. TGF-1 signaling is also sufficient to prevent homeostatic LC migration as mice in which LC express a mutated, constitutively active TGF-RI fail to migrate to regional lymph under steady-state conditions (Fig. 2) 35. TGF-1 is secreted as an inactive, latent form associated with LAP and in the epidermis requires activation by the integrins av6 or av8 that are SGI-1776 ic50 expressed by non-overlapping subsets of keratinocytes (av6 in the interfollicular regions and av8 near the hair follicles) 35,36. Thus, transactivation of LC-derived TGF-1 by integrins expressed by keratinocytes is required to maintain the epidermal residence of LC under non-inflammatory conditions. TGF-1 signaling is required for expression of Axl that has anti-inflammatory effects and may act on LC as well as KC to inhibit migration 28. From this, the inference is reasonably made that keratinocyte expression of av6 or SGI-1776 ic50 av8 likely in conjunction with additional signals may be a required event for homeostatic LC igration. Open in a separate window Figure 2. Keratinocytes and TGF- control LC migrationUnder steady-state conditions, integrins av6 and av8 transactivate LC-derived TGF–LAP. a) Tonic TGF- signaling in LC as well as LC-KC structural interactions are required for their epidermal retention. b) Migratory signals such as UV light reduce KC expression of av6 and av8 reducing the availability of active TGF-. The absence of active TGF- likely in conjunction with still unknown factors results in LC migration. Inflammatory cytokines including IL-1 and TNF from KC and dermal infiltrates also promote LC migration but likely act indirectly on KC. LC self-renew and remain of host origin in murine bone marrow transplantation models18,37,38. LCs can repair DNA damage through the action of the cyclin-dependent kinase inhibitor, CDKN1A, which permits cell cycle arrest, providing protection against ionizing radiation39. However, strong inflammatory stimuli such as UV light can deplete LC10. In this context, CCR2-dependent GR1hi monocytes are recruited into SGI-1776 ic50 the epidermis to replace LC that have migrated (Fig. 1) 10. Recruitment of monocyte precursors into the epidermis occurs at the hair follicle and requires the chemokine.