No abstract

The JAK-STAT signaling pathway has been implicated in mediating biological responses induced by many cytokines. However, cytokines that promote distinct cellular responses often activate identical STAT proteins, thereby raising the question of how specificity is manifest within this signaling pathway. Here we report the generation and characterization of mice deficient in STAT1. STAT1-deficient mice show no overt developmental abnormalities, but display a complete lack of responsiveness to either IFN alpha or IFN gamma and are highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice respond normally to several other cytokines that activate STAT1 in vitro. These observations document that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biologic responses and reveal an unexpected level of physiologic specificity for STAT1 action.

This study demonstrates that endogenously produced interferon ␥ (IFN-␥) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice.

No abstract

Langerhans cells (LCs) are antigen-presenting cells that reside in the epidermis of the skin and traffic to lymph nodes (LNs). The general role of these cells in skin immune responses is not clear because distinct models of LC depletion resulted in opposite conclusions about their role in contact hypersensitivity (CHS) responses. While comparing these models, we discovered a novel population of LCs that resides in the dermis and does not represent migrating epidermal LCs, as previously thought. Unlike epidermal LCs, dermal Langerin+ dendritic cells (DCs) were radiosensitive and displayed a distinct cell surface phenotype. Dermal Langerin+ DCs migrate from the skin to the LNs after inflammation and in the steady state, and represent the majority of Langerin+ DCs in skin draining LNs. Both epidermal and dermal Langerin+ DCs were depleted by treatment with diphtheria toxin in Lang-DTREGFP knock-in mice. In contrast, transgenic hLang-DTA mice lack epidermal LCs, but have normal numbers of dermal Langerin+ DCs. CHS responses were abrogated upon depletion of both epidermal and dermal LCs, but were unaffected in the absence of only epidermal LCs. This suggests that dermal LCs can mediate CHS and provides an explanation for previous differences observed in the two-model systems.

Epidermal Langerhans cells (LCs), a distinct skin-resident dendritic cell population, acquire antigen in the skin and migrate to draining lymph nodes where they are thought to initiate adaptive immune responses. To examine the functional requirement of LCs in skin immunity, we generated BAC transgenic mice in which the regulatory elements from human Langerin were used to drive expression of diphtheria toxin. The resulting mice have a constitutive and durable absence of epidermal LCs but are otherwise intact. Unexpectedly, we found that contact hypersensitivity (CHS) was amplified rather than abrogated in the absence of LCs. Moreover, we showed that LCs act during the priming and not the effector phase. Thus, LCs not only were dispensable for CHS, but they served to regulate the response, a previously unappreciated function.

No abstract

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations on the basis of available evidence.