It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.

The relative contributions of basophils and dendritic cells in Th2 skewing to foreign antigen exposure remain unclear. Here we report the ability of basophils to induce Th2 polarization upon epicutaneous sensitization with different antigens using basophil conditionally depleted Bas TRECK transgenic mice. Basophils are responsible for Th2 skewing to haptens and peptide antigens, but not protein antigens in vivo. Consistent with this, basophils cannot take up or process ovalbumin protein in significant quantities, but present ovalbumin peptide to T cells for Th2 differentiation via major histocompatibility complex class II. Intriguingly, basophils promote Th2 skewing upon ovalbumin protein exposure in the presence of dendritic cells. Taken together, our results suggest that basophils alone are able to induce Th2 skewing with haptens and peptide antigens but require dendritic cells for the induction of Th2 for protein antigens upon epicutaneous immunization.

Atopic dermatitis (AD) is generally regarded as a type 2 helper T (Th2)-mediated inflammatory skin disease. Although the number of IL-17A-producing cells is increased in the peripheral blood and in acute skin lesion of AD patients, the role of IL-17A in the pathogenesis of AD remains unclear. To clarify this issue, we used murine AD models in an IL-17A-deficient condition. In a repeated hapten application-induced AD model, skin inflammation, IL-4 production in the draining lymph nodes (LNs), and hapten-specific IgG1 and IgE induction were suppressed in IL-17A-deficient mice. Vγ4(+) γδ T cells in the skin-draining LNs and Vγ5(-) dermal γδ T cells in the skin were the major sources of IL-17A. Consistently, in flaky-tail (Flg(ft/ft) ma/ma) mice, spontaneous development of AD-like dermatitis and IgE induction were attenuated by IL-17A deficiency. Moreover, Th2 differentiation from naive T cells was promoted in vitro by the addition of IL-17A. Taken together, our results suggest that IL-17A mediates Th2-type immune responses and that IL-17A signal may be a therapeutic target of AD.

Sawada et al. report that Resolvin E1 (RvE1) down-regulates DC motility in both steady state and inflammatory conditions in the skin and exerts its antiinflammatory effects in contact hypersensitivity. They propose the LTB4-BLT1 signaling blockade as a possible major mechanism through which RvE1 exerts its regulatory effects.

The host defense system of the skin is composed of (1) a barrier, (2) innate immunity, and (3) acquired immunity. Inflammatory skin diseases can be classified into one of the disorders of these layers of the defense system, unless there is an ordinary response to specific infectious agents or internal/external injury. Any inflammatory skin disease partly simulates the response to real infections or dangers. Disorders of acquired immunity can be classified into (1) immunodeficiency, (2) immunohyperactivity (allergy), and (3) qualitative disorder (autoimmunity). Disorders of innate immunity can be classified into (1) innate immunodeficiency, (2) innate immunohyperactivity (general or local autoinflammation), and (3) qualitative disorder (general or local innate autoimmunity). The barrier of the skin is composed of (1) the physical barrier and (2) the chemical barrier. Several diseases, such as atopic dermatitis, are attributed to the disorder of these components of the barrier. Here, we propose an algorithm to classify the pathology of inflammatory skin diseases by means of what disorder in the specific layer of the host defense system is truly responsible.