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1.
Cancer Immunol Res ; 11(9): 1266-1279, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37432112

RESUMO

Clec4A4 is a C-type lectin receptor (CLR) exclusively expressed on murine conventional dendritic cells (cDC) to regulate their activation status. However, the functional role of murine Clec4A4 (mClec4A4) in antitumor immunity remains unclear. Here, we show that mClec4A4 serves as a negative immune checkpoint regulator to impair antitumor immune responses. Deficiency of mClec4A4 lead to a reduction in tumor development, accompanied by enhanced antitumor immune responses and amelioration of the immunosuppressive tumor microenvironment (TME) mediated through the enforced activation of cDCs in tumor-bearing mice. Furthermore, antagonistic mAb to human CLEC4A (hCLEC4A), which is the functional orthologue of mClec4A4, exerted protection against established tumors without any apparent signs of immune-related adverse events in hCLEC4A-transgenic mice. Thus, our findings highlight the critical role of mClec4A4 expressed on cDCs as a negative immune checkpoint molecule in the control of tumor progression and provide support for hCLEC4A as a potential target for immune checkpoint blockade in tumor immunotherapy.

2.
Cell Rep ; 42(5): 112431, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37099426

RESUMO

While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11c+CD103+ conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11c+CD103+ cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11c+CD103+ cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11c+CD103+ cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11c+CD103+ cDCs and ILC3s for maintaining the tolerogenesis of CD11c+CD103+ cDCs in MesLNs, responsible for the failed establishment of oral tolerance.


Assuntos
Disbiose , Imunidade Inata , Humanos , Disbiose/metabolismo , Linfócitos/metabolismo , Cadeias alfa de Integrinas/metabolismo , Células Dendríticas/metabolismo , Antibacterianos/metabolismo , Mucosa Intestinal/metabolismo
4.
Front Immunol ; 12: 712676, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394115

RESUMO

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/imunologia
6.
Commun Biol ; 3(1): 742, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288832

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/fisiologia
7.
Sci Rep ; 10(1): 16375, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32989237

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
Int Immunol ; 32(10): 673-682, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32415968

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/imunologia
9.
Sci Rep ; 10(1): 8371, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433498

RESUMO

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 Reversa
10.
Clin Case Rep ; 7(5): 1057-1061, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31110745

RESUMO

The use of mogamulizumab needs careful consideration because of severe adverse reactions such as graft-vs-host disease. However, refractory specific skin lesions of smoldering type adult T-cell leukemia/lymphoma can be effectively treated with mogamulizumab when patients have no opportunity to receive hematopoietic stem cell transplantation like our case.

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