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1.
bioRxiv ; 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38352414

RESUMO

The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

2.
Oncoimmunology ; 13(1): 2297503, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38235319

RESUMO

Activins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls. We observed that both tumor and immune cells could be sources of activins. Importantly, our in vitro studies suggest that activins promote differentiation of naïve CD4+ cells into Foxp3-expressing induced regulatory T cells (Tregs), particularly when TGF-beta was limited in the culture medium. Database and qRT-PCR analysis of sorted major immune cell subsets in mice revealed that activin receptor 1c (ActRIC) was uniquely expressed on Tregs and that both ActRIC and ActRIIB (activin receptor 2b) were highly upregulated during iTreg differentiation. ActRIC-deficient naïve CD4+ cells were found to be defective in iTreg generation both in vitro and in vivo. Treg suppression assays were also performed, and ActRIC deficiency did not change the function or stability of iTregs. Mice lacking ActRIC or mice treated with monoclonal anti-ActRIC antibody were more resistant to tumor progression than wild-type controls. This phenotype was correlated with reduced expression of Foxp3 in CD4+ cells in the tumor microenvironment. In light of the information presented above, blocking activin-ActRIC signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive iTregs in cancer. Therefore, it is a potential candidate for cancer immunotherapy.


Assuntos
Linfócitos T CD4-Positivos , Neoplasias , Humanos , Camundongos , Animais , Receptores de Ativinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Imunoterapia , Neoplasias/terapia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Ativinas/metabolismo , Microambiente Tumoral
3.
Sci Adv ; 7(16)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33863719

RESUMO

The avascular nature of cornea tissue limits its regenerative potential, which may lead to incomplete healing and formation of scars when damaged. Here, we applied micro- and ultrafine porcine urinary bladder matrix (UBM) particulate to promote type 2 immune responses in cornea wounds. Results demonstrated that UBM particulate substantially reduced corneal haze formation as compared to the saline-treated group. Flow cytometry and gene expression analysis showed that UBM particulate suppressed the differentiation of corneal stromal cells into α-smooth muscle actin-positive (αSMA+) myofibroblasts. UBM treatments up-regulated interleukin-4 (IL-4) produced primarily by eosinophils in the wounded corneas and CD4+ T cells in draining lymph nodes, suggesting a cross-talk between local and peripheral immunity. Gata1-/- mice lacking eosinophils did not respond to UBM treatment and had impaired wound healing. In summary, stimulating type 2 immune responses in the wounded cornea can promote proregenerative environments that lead to improved wound healing for vision restoration.


Assuntos
Lesões da Córnea , Bexiga Urinária , Animais , Córnea/patologia , Lesões da Córnea/patologia , Matriz Extracelular/metabolismo , Camundongos , Suínos , Bexiga Urinária/metabolismo , Cicatrização/fisiologia
4.
Clin Cancer Res ; 26(15): 4018-4030, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32332015

RESUMO

PURPOSE: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response. EXPERIMENTAL DESIGN: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies. RESULTS: Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their in situ distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8+ T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue. CONCLUSIONS: Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Complexas Mistas/imunologia , Rabdomiossarcoma/imunologia , Estruturas Linfoides Terciárias/imunologia , Macrófagos Associados a Tumor/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/tratamento farmacológico , Neoplasias Complexas Mistas/genética , Neoplasias Complexas Mistas/patologia , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Estruturas Linfoides Terciárias/patologia , Evasão Tumoral , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem
5.
Sci Transl Med ; 12(539)2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295900

RESUMO

Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyzed fibrotic capsules surrounding surgically excised human breast implants from 12 individuals. We found increased numbers of interleukin 17 (IL17)-producing γδ+ T cells and CD4+ T helper 17 (TH17) cells as well as senescent stromal cells in the fibrotic capsules. Further analysis in a murine model demonstrated an early innate IL17 response to implanted synthetic material (polycaprolactone) particles that was mediated by innate lymphoid cells and γδ+ T cells. This was followed by a chronic adaptive CD4+ TH17 cell response that was antigen dependent. Synthetic materials with varying chemical and physical properties implanted either in injured muscle or subcutaneously induced similar IL17 responses in mice. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to implanted synthetic materials and the development of p16INK4a senescent cells. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model. Discovery of a feed-forward loop between the TH17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response.


Assuntos
Senescência Celular , Corpos Estranhos , Reação a Corpo Estranho , Interleucina-17 , Animais , Feminino , Corpos Estranhos/imunologia , Humanos , Imunidade Inata , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Próteses e Implantes
6.
Front Immunol ; 11: 580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32322254

RESUMO

YAP is a transcriptional coactivator of the Hippo signaling pathway that has largely been studied for its role in the regulation of organ size during development. Several studies have shown that YAP is upregulated in cancer cells, and more recently in the T regulatory (Treg) subset of CD4+ cells. These observations suggest that the transcriptional co-activator may promote tumor persistence and progression. Here, we report that YAP also plays an immunoinhibitory role in CD8 T cells, especially in activated cytotoxic cells usually found in the tumor microenvironment. Our findings add further rationale for the development and use of pharmacologic inhibitors of YAP to treat cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Ciclo Celular/imunologia , Neoplasias/imunologia , Fatores de Transcrição/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Sinalização YAP
7.
EMBO J ; 38(9)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886050

RESUMO

Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6-deficient Tregs were dysfunctional in vivo; mice with Treg-restricted deletion of TRAF6 were resistant to implanted tumors and displayed enhanced anti-tumor immunity. We further determined that FOXP3 undergoes K63-linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. In the absence of TRAF6 activity or upon mutation of the ubiquitination site, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63-linked ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene-regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg-stabilizing regulator that may be targeted in novel tolerance-breaking therapies.


Assuntos
Colite/imunologia , Fatores de Transcrição Forkhead/fisiologia , Lisina/metabolismo , Melanoma Experimental/imunologia , Linfócitos T Reguladores/imunologia , Fator 6 Associado a Receptor de TNF/fisiologia , Ubiquitinação , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
8.
Cancer Discov ; 8(8): 1026-1043, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29907586

RESUMO

Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFß/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target.Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026-43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Experimentais/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Linfócitos T Reguladores/imunologia , Ativinas/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Transdução de Sinais , Fatores de Transcrição , Microambiente Tumoral , Regulação para Cima , Proteínas de Sinalização YAP
10.
Cell Host Microbe ; 23(2): 203-214.e5, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29398651

RESUMO

Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.


Assuntos
Toxinas Bacterianas/imunologia , Bacteroides fragilis/imunologia , Carcinogênese/patologia , Colo/imunologia , Neoplasias Colorretais/etiologia , Células Epiteliais/imunologia , Interleucina-17/imunologia , Metaloendopeptidases/imunologia , Fator de Transcrição RelA/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Toxinas Bacterianas/metabolismo , Bacteroides fragilis/patogenicidade , Linhagem Celular Tumoral , Colo/citologia , Colo/microbiologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Ativação Enzimática/imunologia , Feminino , Deleção de Genes , Células HT29 , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Interleucina-17/genética , Masculino , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-8B/genética , Fator de Transcrição STAT3/metabolismo
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