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1.
Immunity ; 57(7): 1629-1647.e8, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38754432

RESUMO

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.


Assuntos
Autoimunidade , Linfócitos T CD8-Positivos , Diferenciação Celular , Quimiocina CXCL16 , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Lipoproteínas LDL , Macrófagos , Camundongos Endogâmicos NOD , Camundongos Knockout , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Quimiocina CXCL16/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Camundongos Endogâmicos C57BL
2.
Proc Natl Acad Sci U S A ; 120(49): e2312039120, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38015847

RESUMO

In both humans and NOD mice, type 1 diabetes (T1D) develops from the autoimmune destruction of pancreatic beta cells by T cells. Interactions between both helper CD4+ and cytotoxic CD8+ T cells are essential for T1D development in NOD mice. Previous work has indicated that pathogenic T cells arise from deleterious interactions between relatively common genes which regulate aspects of T cell activation/effector function (Ctla4, Tnfrsf9, Il2/Il21), peptide presentation (H2-A g7, B2m), and T cell receptor (TCR) signaling (Ptpn22). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus (Mtv)3 provirus as a genetic element affecting CD4+/CD8+ T cell interactions through an additional mechanism, altering the TCR repertoire. Mtv3 encodes a superantigen (SAg) that deletes the majority of Vß3+ thymocytes in NOD mice. Ablating Mtv3 and restoring Vß3+ T cells has no effect on spontaneous T1D development in NOD mice. However, transferring Mtv3 to C57BL/6 (B6) mice congenic for the NOD H2 g7 MHC haplotype (B6.H2 g7) completely blocks their normal susceptibility to T1D mediated by transferred CD8+ T cells transgenically expressing AI4 or NY8.3 TCRs. The entire genetic effect is manifested by Vß3+CD4+ T cells, which unless deleted by Mtv3, accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8+ T cells. Our findings provide evidence that endogenous Mtv SAgs can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vß repertoire due to Mtvs, it raises questions about the role of Mtvs in other mouse models designed to reflect human immune disorders.


Assuntos
Diabetes Mellitus Tipo 1 , Camundongos , Humanos , Animais , Linfócitos T CD8-Positivos , Camundongos Endogâmicos NOD , Vírus do Tumor Mamário do Camundongo , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T CD4-Positivos , Camundongos Transgênicos
3.
J Immunol ; 210(7): 935-946, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36762954

RESUMO

IL-21 is essential for type 1 diabetes (T1D) development in the NOD mouse model. IL-21-expressing CD4 T cells are present in pancreatic islets where they contribute to T1D progression. However, little is known about their phenotype and differentiation states. To fill this gap, we generated, to our knowledge, a novel IL-21 reporter NOD strain to further characterize IL-21+ CD4 T cells in T1D. IL-21+ CD4 T cells accumulate in pancreatic islets and recognize ß cell Ags. Single-cell RNA sequencing revealed that CD4 T effector cells in islets actively express IL-21 and they are highly diabetogenic despite expressing multiple inhibitory molecules, including PD-1 and LAG3. Islet IL-21+ CD4 T cells segregate into four phenotypically and transcriptionally distinct differentiation states, that is, less differentiated early effectors, T follicular helper (Tfh)-like cells, and two Th1 subsets. Trajectory analysis predicts that early effectors differentiate into both Tfh-like and terminal Th1 cells. We further demonstrated that intrinsic IL-27 signaling controls the differentiation of islet IL-21+ CD4 T cells, contributing to their helper function. Collectively, our study reveals the heterogeneity of islet-infiltrating IL-21+ CD4 T cells and indicates that both Tfh-like and Th1 subsets produce IL-21 throughout their differentiation process, highlighting the important sources of IL-21 in T1D pathogenesis.


Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Camundongos , Animais , Diabetes Mellitus Tipo 1/genética , Linfócitos T CD4-Positivos/patologia , Camundongos Endogâmicos NOD , Ilhotas Pancreáticas/patologia
4.
Clin Immunol ; 264: 110260, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38788885

RESUMO

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.


Assuntos
Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Aparelho Lacrimal , Camundongos Endogâmicos NOD , Síndrome de Sjogren , Animais , Síndrome de Sjogren/imunologia , Camundongos , Linfócitos T CD8-Positivos/imunologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Interleucinas/imunologia , Interleucinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Feminino , Transdução de Sinais/imunologia , Receptores de Interleucina/imunologia , Interleucina-27/metabolismo , Interleucina-27/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Apirase/imunologia , Apirase/metabolismo
5.
J Immunol ; 207(8): 1990-2004, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34507949

RESUMO

In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing ß cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of ß-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR6- and CD44highTCF1-CXCR6+, in islets of prediabetic NOD mice. Compared with CD44highTCF1+CXCR6- CD8 T cells, the CD44highTCF1-CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR6- CD8 T cells, through continuous generation of the CD44highTCF1-CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct IL-27 signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR6- population. These results indicate that islet CD44highTCF1+CXCR6- CD8 T cells are a progenitor-like subset with self-renewing capacity, and, under an IL-27-controlled mechanism, they differentiate into the CD44highTCF1-CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Interleucina-27/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Diferenciação Celular , Autorrenovação Celular , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Células Secretoras de Insulina/imunologia , Camundongos , Camundongos Endogâmicos NOD
6.
Extremophiles ; 26(2): 20, 2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35716203

RESUMO

A novel moderately halophilic, Gram-stain-negative, catalase- and oxidase-positive, strictly aerobic, non-sporulating, non-motile rod, designated strain JSM 104105 T, was isolated from human faeces. Strain JSM 104105 T was able to grow with 0.5-18% (w/v) NaCl (optimum 4-9%), at pH 6-10.5 (optimum pH 7-8) and at 10-40 °C (optimum 30 °C) in complex media. The major cellular fatty acids were C18:1ω7c, C16:0, C16:1ω7c and/or C16:1ω6c, C19:0 cyclo ω8c and C12:0 3-OH. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified aminophospholipid, an unidentified glycolipid and three unidentified phospholipids. The predominant respiratory quinone was Q-9 and the genomic DNA G + C content was 64.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JSM 104105 T should be assigned to the genus Halomonas, and was most closely related to Halomonas gudaonensis SL014B-69 T (99.0% sequence similarity), followed by Halomonas azerbaijanica TBZ202T (98.6%) and Halomonas lysinitropha 3(2)T (97.3%). The whole genomic analysis showed that strain JSM 104105 T constituted a different taxon separated from the recognized Halomonas species. Combined data from phenotypic and genotypic studies demonstrated that strain JSM 104105 T represents a new species of the genus Halomonas, for which the name Halomonas faecis sp. nov. is proposed. The type strain is JSM 104105 T (= CCTCC AB 2014160 T = CGMCC 1.12945 T = KCTC 42146 T).


Assuntos
Halomonas , Técnicas de Tipagem Bacteriana , DNA Bacteriano/genética , Ácidos Graxos/química , Fezes , Humanos , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
7.
J Immunol ; 204(11): 2887-2899, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32295876

RESUMO

CD137 modulates type 1 diabetes (T1D) progression in NOD mice. We previously showed that CD137 expression in CD4 T cells inhibits T1D, but its expression in CD8 T cells promotes disease development by intrinsically enhancing the accumulation of ß-cell-autoreactive CD8 T cells. CD137 is expressed on a subset of FOXP3+ regulatory CD4 T cells (Tregs), and CD137+ Tregs are the main source of soluble CD137. Soluble CD137 suppresses T cells in vitro by binding to the CD137 ligand (CD137L) upregulated on activated T cells. To further study how the opposing functions of CD137 are regulated, we successfully targeted Tnfsf9 (encoding CD137L) in NOD mice using the CRISPR/Cas9 system (designated NOD.Tnfsf9 -/-). Relative to wild-type NOD mice, T1D development in the NOD.Tnfsf9 -/- strain was significantly delayed, and mice developed less insulitis and had reduced frequencies of ß-cell-autoreactive CD8 T cells. Bone marrow chimera experiments showed that CD137L-deficient hematopoietic cells were able to confer T1D resistance. Adoptive T cell transfer experiments showed that CD137L deficiency on myeloid APCs was associated with T1D suppression. Conversely, lack of CD137L on T cells enhanced their diabetogenic activity. Furthermore, neither CD137 nor CD137L was required for the development and homeostasis of FOXP3+ Tregs. However, CD137 was critical for the in vivo T1D-suppressive activity of FOXP3+ Tregs, suggesting that the interaction between CD137 and CD137L regulates their function. Collectively, our results provide new insights into the complex roles of CD137-CD137L interaction in T1D.


Assuntos
Ligante 4-1BB/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Linfócitos T Reguladores/metabolismo , Ligante 4-1BB/genética , Animais , Antígenos CD4/metabolismo , Células Cultivadas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Quimeras de Transplante , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
8.
Arch Microbiol ; 203(8): 5249-5255, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34373934

RESUMO

A Gram-stain-positive, aerobic, nonmotile actinobacterium, designated strain YIM 93776T, was isolated from a saline sediment sample collected from Aiding Lake in Xinjiang Uygur Autonomous Region, Northwest China. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain YIM 93776T was affiliated to the genus Glycomyces and was closely related to Glycomyces albus TRM 49136T (97.6% sequence similarity), Glycomyces lacisalsi XHU 5089T (97.0%) and Glycomyces anabasis EGI 6500139T (96.2%). The cell wall contained meso-diaminopimelic acid and the whole-cell hydrolysates sugars were galactose, mannose, arabinase, glucose and ribose. The predominant menaquinones were MK-9 (H4) and MK-10 (H4). Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, two phosphatidylglyceride, two unidentified phospholipids and two unidentified polar lipids were detected in the polar lipid extracts. Major fatty acids were anteiso-C17:0, iso-C15:0, iso-C16:0, anteiso-C15:0 and anteiso C17:1 A. The draft genome sequence of strain YIM 93776T was 5.37 Mbp in size with 69.5% DNA G + C content. The dDDH and ANI values between strain YIM 93776T and related neighbours were 25.0-34.3% and 77.3-79.8%, respectively. On the basis of morphological, chemotaxonomic and phylogenetic evidence, strain YIM 93776T; therefore, represents a novel species, for which the name Glycomyces salinus sp. nov. is proposed. The type strain is YIM 93776T (= KCTC 49430T = CGMCC 4.7685T).


Assuntos
Actinobacteria , Actinobacteria/genética , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ecossistema , Ácidos Graxos/análise , Fosfolipídeos/análise , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2
9.
Int J Mol Sci ; 22(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916486

RESUMO

Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren's disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development.


Assuntos
Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Interleucinas/imunologia , Aparelho Lacrimal/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucinas/genética , Aparelho Lacrimal/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia
10.
Int J Syst Evol Microbiol ; 70(2): 1139-1144, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751198

RESUMO

A Gram-stain-positive, moderately halophilic, strictly aerobic, endospore-forming, rod-shaped bacterium, strain JSM 102062T, was isolated from a non-saline farm soil sample collected from Dehang Canyon in Hunan, PR China. Growth occurred with 0.5-20 % (w/v) NaCl (optimum 4-7 %) at pH 5.5-11.0 (optimum pH 8.0) and at 20-50 °C (optimum 30-35 °C). Contained cell-wall peptidoglycan based on meso-diaminopimelic acid and possessed menaquinone-7 (MK-7) as the major respiratory isoprenoid quinone. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The polar lipid pattern consisted of diphosphatidylglycerol, phosphatidylglycerol, five unidentified phospholipids and an unidentified glycolipid. The DNA G+C content was 44.1 mol%. Phylogeny based on 16S rRNA gene sequences indicated that strain JSM 102062T belonged to the genus Sediminibacillus, sharing high 16S rRNA gene sequence similarities to Sediminibacillus halophilus EN8dT (99.4 %) and Sediminibacillus albus NHBX5T (98.3 %). The whole genomic analysis showed that strain JSM 102062T constituted a different taxon separated from the recognized Sediminibacillus species. Combined data from phenotypic and genotypic studies demonstrated that strain JSM 102062T represents a noval species of the genus Sediminibacillus, for which the name Sediminibacillus terrae sp. nov. is proposed; the type strain is JSM 102062T (=CCTCC AB 2014166T = CGMCC 1.12957T=DSM 28949T=KCTC 33541T).


Assuntos
Bacillaceae/classificação , Fazendas , Filogenia , Microbiologia do Solo , Bacillaceae/isolamento & purificação , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Graxos/química , Peptidoglicano/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
11.
J Immunol ; 201(7): 1907-1917, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30127089

RESUMO

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T cells recognizing pancreatic ß cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-Kd and/or H2-Db class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8+ T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T cells. Using an inducible model of thymic negative selection and mRNA transcript analyses, we initially identified an elevated Nfkbid expression variant as a likely NOD-proximal chromosome 7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T cells. These results indicated that allelic variants of Nfkbid contribute to the efficiency of intrathymic deletion of diabetogenic CD8+ T cells. However, although enhancing thymic deletion of pathogenic CD8+ T cells, ablating Nfkbid expression surprisingly accelerated T1D onset that was associated with numeric decreases in both regulatory T and B lymphocytes in NOD mice.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Cromossomos Humanos Par 7/genética , Diabetes Mellitus Tipo 1/imunologia , Proteínas I-kappa B/genética , Timo/imunologia , Alelos , Animais , Autoantígenos/imunologia , Diferenciação Celular , Células Cultivadas , Deleção Clonal , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Proteínas I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Polimorfismo Genético
12.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322152

RESUMO

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Aparelho Lacrimal/imunologia , Glicoproteínas de Membrana/imunologia , Síndrome de Sjogren/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Linfócitos B/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interferon Tipo I/metabolismo , Aparelho Lacrimal/citologia , Aparelho Lacrimal/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , RNA-Seq , Glândulas Salivares/citologia , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Sexo , Receptor 7 Toll-Like/genética
13.
J Immunol ; 198(10): 3857-3868, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28363905

RESUMO

We previously reported that CD137 (encoded by Tnfrsf9) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed. In this study, we show that NOD.Tnfrsf9-/- CD8 T cells had significantly reduced diabetogenic capacity, whereas absence of CD137 in non-T and non-B cells had a limited impact on T1D progression. In contrast, NOD.Tnfrsf9-/- CD4 T cells highly promoted T1D development. We further demonstrated that CD137 was important for the accumulation of ß cell-autoreactive CD8 T cells but was dispensable for their activation in pancreatic lymph nodes. The frequency of islet-infiltrating CD8 T cells was reduced in NOD.Tnfrsf9-/- mice in part because of their decreased proliferation. Furthermore, CD137 deficiency did not suppress T1D development in NOD mice expressing the transgenic NY8.3 CD8 TCR. This suggests that increased precursor frequency of ß cell-autoreactive CD8 T cells in NY8.3 mice obviated a role for CD137 in diabetogenesis. Finally, blocking CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice. Collectively, our results indicate that one important diabetogenic function of CD137 is to promote the expansion and accumulation of ß cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Ligante 4-1BB/antagonistas & inibidores , Ligante 4-1BB/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Progressão da Doença , Células Secretoras de Insulina/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
14.
Diabetologia ; 61(11): 2356-2370, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30167736

RESUMO

AIMS/HYPOTHESIS: The study aimed to determine whether discrete subtypes of type 1 diabetes exist, based on immunoregulatory profiles at clinical onset, as this has significant implications for disease treatment and prevention as well as the design and analysis of clinical trials. METHODS: Using a plasma-based transcriptional bioassay and a gene-ontology-based scoring algorithm, we examined local participants from the Children's Hospital of Wisconsin and conducted an ancillary analysis of TrialNet CTLA4-Ig trial (TN-09) participants. RESULTS: The inflammatory/regulatory balance measured during the post-onset period was highly variable. Notably, a significant inverse relationship was identified between baseline innate inflammatory activity and stimulated C-peptide AUC measured at 3, 6, 12, 18 and 24 months post onset among placebo-treated individuals (p ≤ 0.015). Further, duration of persistent insulin secretion was negatively related to baseline inflammation (p ≤ 0.012) and positively associated with baseline abundance of circulating activated regulatory T cells (CD4+/CD45RA-/FOXP3high; p = 0.016). Based on these findings, data from participants treated with CTLA4-Ig were stratified by inflammatory activity at onset; in this way, we identified pathways and transcripts consistent with inhibition of T cell activation and enhanced immunoregulation. Variance among baseline plasma-induced signatures of TN-09 participants was further examined with weighted gene co-expression network analysis and related to clinical metrics. Four age-independent subgroups were identified that differed in terms of baseline innate inflammatory/regulatory bias, rate of C-peptide decline and response to CTLA4-Ig treatment. CONCLUSIONS/INTERPRETATION: These data support the existence of multiple type 1 diabetes subtypes characterised by varying levels of baseline innate inflammation that are associated with the rate of C-peptide decline. DATA AVAILABILITY: Gene expression data files are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE102234).


Assuntos
Abatacepte/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/imunologia , Imunidade Inata/fisiologia , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/mortalidade , Feminino , Citometria de Fluxo , Humanos , Imunidade Inata/genética , Secreção de Insulina/efeitos dos fármacos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Adulto Jovem
15.
Eur J Immunol ; 46(4): 1030-46, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26692253

RESUMO

It was hypothesized that IL-1 antagonism would preserve ß-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1ß additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Inflamação/imunologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1alfa/imunologia , Interleucina-1beta/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados , Células Cultivadas , Diabetes Mellitus Tipo 1/imunologia , Humanos , Imunoterapia/métodos , Células Secretoras de Insulina/fisiologia , Interleucina-1beta/imunologia , Masculino
16.
Immunogenetics ; 69(3): 193-198, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27796442

RESUMO

Type 1 diabetes (T1D) results from complex interactions between genetic and environmental factors. The nonobese diabetic (NOD) mouse develops spontaneous T1D and has been used extensively to study the genetic control of this disease. T1D is suppressed in NOD mice congenic for the C57BL/10 (B10)-derived Idd9 resistance region on chromosome 4. Previous studies conducted by other investigators have identified four subregions (Idd9.1, Idd9.2, Idd9.3, and Idd9.4) where B10-derived genes suppress T1D development in NOD mice. We independently generated and characterized six congenic strains containing B10-derived intervals that partially overlap with the Idd9.1 and Idd9.4 regions. T1D incidence studies have revealed a new B10-derived resistance region proximal to Idd9.1. Our results also indicated that a B10-derived gene(s) within the Idd9.4 region suppressed the diabetogenic activity of CD4 T cells and promoted CD103 expression on regulatory T cells indicative of an activated phenotype. In addition, we suggest the presence of a B10-derived susceptibility gene(s) in the Idd9.1/Idd9.4 region. These results provide additional information to improve our understanding of the complex genetic control by the Idd9 region.


Assuntos
Mapeamento Cromossômico/métodos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Loci Gênicos/genética , Predisposição Genética para Doença , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia
17.
J Immunol ; 195(7): 3011-9, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26283479

RESUMO

NOD-scid.Il2rg(null) (NSG) mice are currently being used as recipients to screen for pathogenic autoreactive T cells in type 1 diabetes (T1D) patients. We questioned whether the restriction of IL-2R γ-chain (Il-2rγ)-dependent cytokine signaling only to donor cells in NSG recipients differently influenced the activities of transferred diabetogenic T cells when they were introduced as a monoclonal/oligoclonal population versus being part of a polyclonal repertoire. Unexpectedly, a significantly decreased T1D transfer by splenocytes from prediabetic NOD donors was observed in Il-2rγ(null)-NSG versus Il-2rγ-intact standard NOD-scid recipients. In contrast, NOD-derived monoclonal/oligoclonal TCR transgenic ß cell-autoreactive T cells in either the CD8 (AI4, NY8.3) or CD4 (BDC2.5) compartments transferred disease significantly more rapidly to NSG than to NOD-scid recipients. The reduced diabetes transfer efficiency by polyclonal T cells in NSG recipients was associated with enhanced activation of regulatory T cells (Tregs) mediated by NSG myeloid APC. This enhanced suppressor activity was associated with higher levels of Treg GITR expression in the presence of NSG than NOD-scid APC. These collective results indicate NSG recipients might be efficiently employed to test the activity of T1D patient-derived ß cell-autoreactive T cell clones and lines, but, when screening for pathogenic effectors within polyclonal populations, Tregs should be removed from the transfer inoculum to avoid false-negative results.


Assuntos
Transferência Adotiva , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Receptores de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/biossíntese , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Interleucina-2/genética , Transdução de Sinais/imunologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/transplante
18.
Diabetologia ; 59(3): 414-25, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26699650

RESUMO

Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 1/genética , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia
19.
Cytokine ; 82: 95-101, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26778709

RESUMO

IL-15 is a member of the gamma chain family of cytokines (γc - CD132). The IL-15 receptor (IL-15R) complex consists of 3 subunits: the ligand-binding IL-15Rα chain (CD215), the ß chain (CD122; also used by IL-2), and the common γ chain. The biological activities of IL-15 are mostly mediated by the IL-15:IL-15Rα complex, produced by the same cell and 'trans-presented' to responder cells expressing the IL-15Rßγc. The peculiar and almost unique requirement for IL-15 to be trans-presented by IL-15Rα suggests that the biological effects of IL-15 signaling are tightly regulated even at the level of availability of IL-15. Tissue-specific deletion of IL-15Rα has shown macrophage-and dendritic cell-derived IL-15Rα mediate the homeostasis of different CD8(+) T cell subsets. Here we show that hepatocyte and macrophage- specific expression of IL-15Rα is required to maintain the homeostasis of NK and NKT cells in the liver. Thus, homeostasis of IL-15-dependent lymphocyte subsets is also regulated by trans-presentation of IL-15 by non-hematopoietic cells in the tissue environment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Homeostase/imunologia , Interleucina-15/imunologia , Fígado/imunologia , Transdução de Sinais/imunologia , Animais , Células Dendríticas/imunologia , Homeostase/genética , Interleucina-15/genética , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/imunologia , Transdução de Sinais/genética
20.
Cytokine ; 82: 102-11, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26868085

RESUMO

Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8(+) T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepatócitos/imunologia , Memória Imunológica , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Animais , Quimiocinas/genética , Quimiocinas/imunologia , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Interleucina-15/genética , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Receptores de Interleucina-15/imunologia
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