RESUMO
A prominent feature of sensitizing environmental compounds that cause allergic contact dermatitis is the rapid induction of an innate inflammatory response that seems to provide danger signals for efficient T cell priming. We generated mouse models of mast cell deficiency, mast cell-specific gene inactivation, and mast cell reporter mice for intravital imaging and showed that these adjuvant effects of contact allergens are mediated by mast cells and histamine. Mast cell deficiency resulted in impaired emigration of skin DCs to the lymph node and contact hypersensitivity was dramatically reduced in the absence of mast cells. In addition, mast cell-specific inactivation of the Il10 gene did not reveal any role for mast cell-derived IL-10 in the regulation of contact allergy. Collectively, we demonstrate that mast cells are essential promoters of contact hypersensitivity, thereby highlighting their potential to promote immune responses to antigens entering via the skin.
Assuntos
Adjuvantes Imunológicos/farmacologia , Dermatite Alérgica de Contato/imunologia , Haptenos/imunologia , Mastócitos/imunologia , Animais , Movimento Celular , Células Dendríticas/imunologia , Histamina/imunologia , Hipertrofia/imunologia , Imunidade Inata , Linfonodos/imunologia , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/imunologiaRESUMO
Regulatory mechanisms initiated by allergen-specific immunotherapy are mainly attributed to T cell derived IL-10. However, it has not been shown that T cell derived IL-10 is required for successful tolerance induction (TI). Here, we analyze cellular sources and the functional relevance of cell type specific IL-10 during TI in a murine model of allergic airway inflammation. While TI was effective in IL-10 competent mice, neutralizing IL-10 prior to tolerogenic treatment completely abrogated the beneficial effects. Cellular sources of IL-10 during TI were identified by using transcriptional reporter mice as T cells, B cells, and to a lesser extent DCs. Interestingly, TI was still effective in mice with T cell, B cell, B and T cell, or DC-specific IL-10 deficiency. In contrast, TI was not possible in mice lacking IL-10 in all hematopoetic cells, while it was effective in bone marrow (BM) chimera that lacked IL-10 only in nonhematopoetic cells. Taken together, allergen-specific tolerance depends on IL-10 from hematopoetic sources. The beneficial effects of allergen-specific immunotherapy cannot solely be attributed to IL-10 from T cells, B cells, or even DCs, suggesting a high degree of cellular redundancy in IL-10-mediated tolerance.
Assuntos
Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Tolerância Imunológica , Inflamação/imunologia , Interleucina-10/genética , Linfócitos T Reguladores/imunologia , Alérgenos/imunologia , Animais , Linfócitos B/imunologia , Dessensibilização Imunológica , Interleucina-10/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with the risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that interleukin-10 (IL-10) deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, macrophage inflammatory protein-1ß/CCL4, and granulocyte colony-stimulating factor). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B-cell neoplasms in a dose-dependent manner and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create a risk for leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.
Assuntos
Interleucina-10/sangue , Leucemia de Células B , Leucemia Linfocítica Crônica de Células B , Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Criança , Modelos Animais de Doenças , Humanos , Interleucina-10/genética , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8(+) T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.
Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Interleucina-10/fisiologia , Animais , Subpopulações de Linfócitos B/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Modelos Animais de Doenças , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Mediadores da Inflamação/fisiologia , Interleucina-10/biossíntese , Interleucina-10/deficiência , Interleucina-10/genética , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Muromegalovirus/imunologia , Células NIH 3T3RESUMO
Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia.