RESUMO
C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) with a characteristic carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces negative signals. However, how CLEC4A exerts cellular inhibition remains unclear. Here, we report that the self-interaction of CLEC4A through the CRD is required for the ITIM-mediated suppressive function in conventional dendritic cells (cDCs). Human type 2 cDCs (cDC2) and monocytes display a higher expression of CLEC4A than cDC1 and plasmacytoid DCs (pDCs) as well as B cells. The extracellular portion of CLEC4A specifically binds to a murine cDC cell line expressing CLEC4A, while its extracellular portion lacking the N-glycosylation site or the EPS motif within the CRD reduces their association. Furthermore, the deletion of the EPS motif within the CRD or ITIM in CLEC4A almost completely impairs its suppressive effect on the activation of the murine cDC cell line, whereas the absence of the N-glycosylation site within the CRD exhibits partial inhibition on their activation. On the other hand, antagonistic monoclonal antibody (mAb) to CLEC4A, which inhibits the self-interaction of CLEC4A and its downstream signaling in murine transfectants, enhances the activation of monocytes and monocyte-derived immature DCs upon stimulation with a Toll-like receptor (TLR) ligand. Thus, our findings suggest a pivotal role of the CRD in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory signal for the control of the function of cDCs.
Assuntos
Carboidratos/imunologia , Lectinas Tipo C/imunologia , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Animais , Células Dendríticas/imunologia , Humanos , Motivo de Ativação do Imunorreceptor Baseado em Tirosina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Reconhecimento de Padrão/imunologiaRESUMO
BACKGROUND: Exposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell-mediated immunity. Although oral tolerance is an active process that involves emergence of CD4+ forkhead box p3 (Foxp3)+ regulatory T (Treg) cells in gut-associated lymphoid tissues (GALTs) for suppression of effector T (Teff) cells, how antigen-presenting cells initiate this process remains unclear. OBJECTIVE: We sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance. METHODS: GALT-associated pDCs in wild-type mice were examined for their ability to induce differentiation of CD4+ Teff cells and CD4+Foxp3+ Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4+Foxp3+ Treg cells and induction of oral tolerance to protect against Teff cell-mediated allergic inflammation. RESULTS: GALT-associated pDCs preferentially generate CD4+Foxp3+ Treg cells rather than CD4+ Teff cells, and such generation requires an autocrine loop of TGF-ß for its robust production. A deficiency of pDCs abrogates antigen-specific de novo generation of CD4+Foxp3+ Treg cells occurring in GALT after antigenic feeding. Furthermore, the absence of pDCs impairs development of oral tolerance, which ameliorates the progression of delayed-type hypersensitivity and systemic anaphylaxis, as well as allergic asthma, accompanied by an enhanced antigen-specific CD4+ Teff cell response and antibody production. CONCLUSION: pDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis.
Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Tecido Linfoide/imunologia , CamundongosRESUMO
Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of Thelper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Here, we describe the impact of the constitutive loss of cDCs on the progression of AD-like inflammation by using binary transgenic (Tg) mice that constitutively lacked CD11chi cDCs. Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of Staphylococcus aureus (S. aureus), that associated with disease flare. Thus, cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.
Assuntos
Células Dendríticas/patologia , Dermatite Atópica/congênito , Imunidade Adaptativa , Animais , Antígenos CD11/análise , Calcitriol/análogos & derivados , Calcitriol/uso terapêutico , Contagem de Células , Citocinas/imunologia , Células Dendríticas/química , Células Dendríticas/imunologia , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Fármacos Dermatológicos/uso terapêutico , Progressão da Doença , Suscetibilidade a Doenças , Eczema/imunologia , Eczema/patologia , Retroalimentação Fisiológica , Homeostase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Organismos Livres de Patógenos Específicos , Infecções Cutâneas Estafilocócicas/etiologia , Staphylococcus aureus/patogenicidade , Células Th2/imunologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4+Foxp3+ regulatory T (Treg) cells abrogates the protective effect of SLIT against allergic disorders. Furthermore, sublingual antigenic application primarily induces antigen-specific CD4+Foxp3+ Treg cells in draining ManLNs, in which it is severely impaired in the absence of cDCs. In ManLNs, migratory CD11b+ cDCs are superior to other conventional dendritic cell subsets for the generation of antigen-specific CD4+Foxp3+ Treg cells, which is reflected by their dominancy in the tolerogenic features to favor this program. Thus, ManLNs are privileged sites in triggering mucosal tolerance mediating protect effect of SLIT on allergic disorders that requires a tolerogenesis of migratory CD11b+ conventional dendritic cells.
Assuntos
Células Dendríticas/fisiologia , Hipersensibilidade/terapia , Imunoterapia/métodos , Linfonodos/citologia , Ovalbumina/imunologia , Animais , Especificidade de Anticorpos , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Imunidade Celular , Imunização , Imunoglobulinas/metabolismo , Camundongos , Ovalbumina/toxicidade , Linfócitos T Reguladores/fisiologiaRESUMO
The integrin αE known as CD103 binds integrin ß7 to form the complete heterodimeric integrin molecule αEß7. CD103 is mainly expressed by lymphocytes within epithelial tissues of intestine, lung, and skin as well as subsets of mucosal and dermal conventional dendritic cells (cDCs). CD103 has been originally implicated in the attachment of lymphocytes to epithelium in the gut and skin through the interaction with E-cadherin expressed on intestinal epithelial cells, keratinocytes, and Langerhans cells (LCs). However, an impact of CD103 on the cutaneous immune responses and the development of inflammatory skin diseases remains elusive. Here, we report that CD103 regulates the development of psoriasiform dermatitis through the control of the function of cDCs. Deficiency in CD103 exacerbates psoriasiform dermatitis, accompanied by excessive epidermal hyperplasia and infiltration of inflammatory leukocytes. Furthermore, deficiency in CD103 not only accelerates the production of proinflammatory cytokines in psoriatic lesions but also promotes the generation of lymphocytes producing interleukin (IL)-17 in the skin-draining peripheral lymph nodes (PLNs). Under the deficiency in CD103, cDCs localized in PLNs enhance cytokine production following activation. Thus, our findings reveal a pivotal role for CD103 in the control of the function of cDCs to regulate cutaneous inflammation in psoriasiform dermatitis.
Assuntos
Antígenos CD/metabolismo , Dermatite/metabolismo , Cadeias alfa de Integrinas/metabolismo , Psoríase/metabolismo , Animais , Antígenos CD/genética , Autoimunidade/genética , Autoimunidade/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Dermatite/genética , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Cadeias alfa de Integrinas/genética , Queratinócitos/metabolismo , Células de Langerhans/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Psoríase/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.