A Phenotypic Analysis of Involucrin-Membrane-Bound Ovalbumin Mice after Adoptive Transfer of Ovalbumin-Specific CD8⁺ T Cells

To investigate the mechanism of autoimmunity and peripheral tolerance in the skin, several transgenic mouse strains expressing membrane-bound ovalbumin (mOVA) as an epidermal self-antigen under the control of keratinocyte-specific promotors, such as keratin 5 and keratin 14, were employed in combination with adoptive transfer of CD8⁺ T cells from OT-I mice (OT-I T cells) that recognize an ovalbumin-derived peptide. However, these strains showed bodyweight loss and required additional inflammatory stimuli, such as γ-irradiation and tape-stripping, to induce skin inflammation. In this study, we generated a mouse strain expressing mOVA under the control of human involucrin promoter (involucrin-mOVA mice). In contrast to previous strains, involucrin-mOVA mice spontaneously developed skin inflammation after the transfer of OT-I T cells in the absence of external stimuli without significant bodyweight loss. We focused on the skin infiltration process of OT-I T cells and found that transferred OT-I T cells accumulated around the hair follicles in the early phase of skin inflammation, and in the later phase, the skin inflammation spontaneously resolved despite the remaining OT-I T cells in the skin. Our involucrin-mOVA mice will provide a promising tool to investigate the pathogenesis and the tolerance mechanisms of cytotoxic skin autoimmunity

SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells

Basophils are required for the induction of Th2 immunity to haptens and peptide antigens

ハプテンやペプチド抗原に対するTh2誘導に好塩基球が必須である. 京都大学プレスリリース. 2013-04-24.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

Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model

Ablファミリーチロシンキナーゼが抗体の血管外輸送を制御することを解明 --生体内での抗体輸送メカニズム--. 京都大学プレスリリース. 2019-10-21.The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders

Dermal Vγ4(+) γδ T cells possess a migratory potency to the draining lymph nodes and modulate CD8(+) T-cell activity through TNF-α production.

A large number of gamma delta T cells (γδ T cells) are located within epithelial tissues including the skin. In mice, epidermal and dermal γδ T cells consist of distinct subsets and have specific roles in cutaneous immune responses. A recent study demonstrated that γδ T cells and cutaneous dendritic cells migrate from the skin to the draining lymph nodes (LNs). However, it remains unclear whether they regulate the antigen-specific immune response within the LNs. Herein, we investigated their properties and role in the LNs using the Mycobacterium bovis bacille Calmette-Guérin (BCG) infection model. In vivo cell labeling analysis revealed that most of the migratory subset comprised dermal Vγ4(+) cells. This population transmigrated from the skin to the LNs in a Gi-coupled chemokine receptor-independent manner. By depleting Vγ4(+) cells, the intranodal expansion of CD8(+) T cell against BCG was significantly attenuated. In addition, in vitro analysis revealed that Vγ4(+) cells produced TNF-α and enhanced IL-12 production by dendritic cells. Taken together, these findings suggest that dermal Vγ4(+) cells are a unique subset that possesses a migratory potency to the skin-draining LNs and enhances the dendritic cell function therein

High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing γδ T cells

Abstract Psoriasis is a common, chronic inflammatory skin disease characterized by epidermal hyperplasia via the IL-23/IL-17 axis. Various studies have indicated the association between obesity and psoriasis, however, the underlying mechanisms remains unclarified. To this end, we focused on high-fat diet (HFD) in this study, because HFD is suggested as a contributor to obesity, and HFD-fed mice exhibit exacerbated psoriatic dermatitis. Using murine imiquimod (IMQ)-induced psoriasis and HFD-induced obesity models, we have revealed a novel mechanism of HFD-induced exacerbation of psoriatic dermatitis. HFD-fed mice exhibited aggravated psoriatic dermatitis, which was accompanied with increased accumulation of IL-17A-producing Vγ4+ γδ T cells in the skin. HFD also induced the increase of Vγ4+ γδ T cells in other organs such as skin draining lymph nodes, which preceded the increase of them in the skin. In addition, HFD-fed mice displayed increased expression of several γδ T cell-recruiting chemokines in the skin. On the other hand, ob/ob mice, another model of murine obesity on normal diet, did not exhibit aggravated psoriatic dermatitis nor accumulation of γδ T cells in the dermis. These results indicate that HFD is a key element in exacerbation of IMQ-induced psoriatic dermatitis, and further raise the possibility of HFD as a factor that links obesity and psoriasis

Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

魚油に多く含まれるオメガ3脂肪酸が皮膚アレルギー反応を抑制する機序の解明. 京都大学プレスリリース. 2015-10-06.Resolvin E1 (RvE1) is a lipid mediator derived from ω3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two-photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade