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1.
Hematol Oncol ; 39 Suppl 1: 15-23, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105821

RESUMO

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas , Histiocitose de Células de Langerhans , Medicina de Precisão , Linfócitos T , Substituição de Aminoácidos , Diferenciação Celular/genética , Movimento Celular/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
2.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063669

RESUMO

Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this relationship because activated and differentiated B cells produce secretory immunoglobulin A (sIgA), which binds commensals to preserve a healthy microbial ecosystem. Mounting evidence shows that changes in the function and composition of the gut microbiota are associated with several autoimmune diseases suggesting that an imbalanced or dysbiotic microbiota contributes to autoimmune inflammation. Bacteria within the gut mucosa may modulate autoimmune inflammation through different mechanisms from commensals ability to induce B-cell clones that cross-react with host antigens or through regulation of B-cell subsets' capacity to produce cytokines. Commensal signals in the gut instigate the differentiation of IL-10 producing B cells and IL-10 producing IgA+ plasma cells that recirculate and exert regulatory functions. While the origin of the dysbiosis in autoimmunity is unclear, compelling evidence shows that specific species have a remarkable influence in shaping the inflammatory immune response. Further insight is necessary to dissect the complex interaction between microorganisms, genes, and the immune system. In this review, we will discuss the bidirectional interaction between commensals and B-cell responses in the context of autoimmune inflammation.


Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Inflamação/genética , Microbiota/imunologia , Autoimunidade/genética , Linfócitos B/patologia , Diferenciação Celular/imunologia , Humanos , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Inflamação/imunologia , Interleucina-10/genética , Microbiota/genética
3.
Nat Commun ; 12(1): 3182, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075041

RESUMO

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-ß1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.


Assuntos
Receptores ErbB/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-9/genética , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Linfócitos T Auxiliares-Indutores/imunologia , Anfirregulina/metabolismo , Animais , Diferenciação Celular/imunologia , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Melanoma Experimental/imunologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Cultura Primária de Células , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Ácido Succínico/metabolismo , Linfócitos T Auxiliares-Indutores/transplante , Ativação Transcricional/imunologia
4.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072618

RESUMO

Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene (Rag) 1 and Rag2 (Rag1/2), whose expression is strictly controlled in a cell type-specific manner; the expression of Rag1/2 genes represents a hallmark of lymphoid lineage commitment. Although Rag genes are known to be evolutionally conserved among jawed vertebrates, how Rag genes are regulated by lineage-specific transcription factors (TFs) and how their regulatory system evolved among vertebrates have not been fully elucidated. Here, we reviewed the current body of knowledge concerning the cis-regulatory elements (CREs) of Rag genes and the evolution of the basic helix-loop-helix TF E protein regulating Rag gene CREs, as well as the evolution of the antagonist of this protein, the Id protein. This may help to understand how the adaptive immune system develops along with the evolution of responsible TFs and enhancers.


Assuntos
Imunidade Adaptativa/genética , Elementos Facilitadores Genéticos , Evolução Molecular , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica , Humanos , Sequências Reguladoras de Ácido Nucleico , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Transcrição/metabolismo , Recombinação V(D)J
5.
Front Immunol ; 12: 620386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936035

RESUMO

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual's immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Adulto , Antígenos CD/metabolismo , Biomarcadores , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/metabolismo , Citotoxicidade Imunológica , Feminino , Perfilação da Expressão Gênica , Humanos , Memória Imunológica , Imunofenotipagem , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
6.
Front Immunol ; 12: 620437, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936036

RESUMO

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.


Assuntos
Autoimunidade , Diferenciação Celular/imunologia , Imunomodulação/genética , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
7.
Nat Commun ; 12(1): 2965, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017005

RESUMO

Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that "deviate" from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.


Assuntos
Neoplasias/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos , Linfócitos T/imunologia , Viroses/imunologia , Animais , Diferenciação Celular/imunologia , Estudos de Coortes , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/sangue , Neoplasias/patologia , Valores de Referência , Software , Especificidade da Espécie , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Viroses/sangue
8.
Front Immunol ; 12: 535039, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815354

RESUMO

The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8+ T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs in vitro. However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made in vitro, the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8α, Granzyme B and perforin in vivo. Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Memória Imunológica/imunologia , Proteínas de Neoplasias/imunologia , Proteínas Repressoras/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia
9.
Front Immunol ; 12: 610789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815365

RESUMO

Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras-MEK-MAPK, JAK-STAT5, and PI3K-ATK-mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.


Assuntos
Diferenciação Celular , Interleucina-15/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interleucina-15/genética , Células Matadoras Naturais/imunologia , Linfopoese/genética , Linfopoese/imunologia , Transdução de Sinais , Fatores de Transcrição/genética
10.
mBio ; 12(2)2021 04 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1195824

RESUMO

New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to gamma interferon (IFN-γ) or nutrient/oxygen deprivation of in vitro-infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analyzed their corresponding CD4 T cell phenotype and vaccine protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination, and against the overexpressing strain, vaccination with MPT70 conferred protection similar to vaccination with ESAT-6. Together, our data indicate that high in vivo antigen expression drives T cells toward terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune balance in favor of the host.IMPORTANCE Tuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current coronavirus disease 2019 (COVID-19) pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunization with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/farmacologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/microbiologia , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Genes Bacterianos , Humanos , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/genética , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/microbiologia
11.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925530

RESUMO

Regulatory B (Breg) cells are endowed with immune suppressive functions. Various human and murine Breg subtypes have been reported. While interleukin (IL)-10 intracellular staining remains the most reliable way to identify Breg cells, this technique hinders further essential functional studies. Recent findings suggest that CD9 is an effective surface marker of murine IL-10 competent Breg cells. However, the stability of CD9 and its relevance as a unique marker for human Breg cells, which have been widely characterized as CD24hiCD38hi, have not been investigated. Here, we demonstrate that CD9 expression is sensitive to in vitro B cell stimulations. CD9 expression could either be re-expressed or downregulated in purified CD9-negative B cells and CD9-positive B cells, respectively. We found no significant differences in the Breg differentiation capacity of the CD9-negative and CD9-positive B cells. Furthermore, CD9-positive B cells co-express CD40 and CD86, suggesting their nature as B cell activation or co-stimulatory molecules, rather than regulatory ones. Therefore, we report the relatively unstable CD9 as a distinct surface molecule, indicating the need for further research for a more reliable marker to purify human Breg cells.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Linfócitos B Reguladores/imunologia , Antígeno CD24/imunologia , Glicoproteínas de Membrana/imunologia , Tetraspanina 29/imunologia , Tecido Adiposo/citologia , Biomarcadores/análise , Diferenciação Celular/imunologia , Criança , Humanos , Interleucina-10/imunologia , Ativação Linfocitária , Células-Tronco Mesenquimais/imunologia , Tonsila Palatina/citologia , Regulação para Cima
12.
Nat Commun ; 12(1): 2308, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863906

RESUMO

Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Imunidade Inata , Timócitos/imunologia , Timo/imunologia , Animais , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Transgênicos , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Timócitos/metabolismo , Timo/citologia
13.
Front Immunol ; 12: 589200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841391

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice in vivo while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4+ T cells and splenocytes in vitro, respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP's function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above in vivo and in vitro studies with FcγR2B-/- mice, indicating that FcγR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcγR2B, and then NF-κB and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.


Assuntos
Apresentação do Antígeno/imunologia , Proteína C-Reativa/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunomodulação , Células Th17/imunologia , Células Th17/metabolismo , Animais , Antígeno B7-2/metabolismo , Biomarcadores , Diferenciação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Camundongos , Monócitos , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Receptores de IgG/metabolismo , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
mBio ; 12(2)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879592

RESUMO

New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to gamma interferon (IFN-γ) or nutrient/oxygen deprivation of in vitro-infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analyzed their corresponding CD4 T cell phenotype and vaccine protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination, and against the overexpressing strain, vaccination with MPT70 conferred protection similar to vaccination with ESAT-6. Together, our data indicate that high in vivo antigen expression drives T cells toward terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune balance in favor of the host.IMPORTANCE Tuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current coronavirus disease 2019 (COVID-19) pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunization with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/farmacologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/microbiologia , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Genes Bacterianos , Humanos , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/genética , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/microbiologia
15.
Nat Commun ; 12(1): 2029, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795689

RESUMO

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor ß chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1ß induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1ß to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1ßR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.


Assuntos
Citocinas/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células T Invariantes Associadas à Mucosa/citologia , Células T Invariantes Associadas à Mucosa/metabolismo , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806895

RESUMO

Skeletal muscle regeneration is highly dependent on the inflammatory response. A wide variety of innate and adaptive immune cells orchestrate the complex process of muscle repair. This review provides information about the various types of immune cells and biomolecules that have been shown to mediate muscle regeneration following injury and degenerative diseases. Recently developed cell and drug-based immunomodulatory strategies are highlighted. An improved understanding of the immune response to injured and diseased skeletal muscle will be essential for the development of therapeutic strategies.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Músculo Esquelético/fisiologia , Regeneração/imunologia , Fatores Etários , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Suscetibilidade a Doenças , Humanos , Imunomodulação , Leucócitos/imunologia , Leucócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803441

RESUMO

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.


Assuntos
Doenças Autoimunes , Linfócitos T CD4-Positivos , Diferenciação Celular , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Transcrição Genética/imunologia , Uveíte , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Uveíte/genética , Uveíte/imunologia , Uveíte/metabolismo , Uveíte/patologia
18.
Front Immunol ; 12: 616583, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692790

RESUMO

Epinephrine is a hormone secreted primarily by medullary cells of the adrenal glands which regulates permeability of blood-brain barrier (BBB). Recent studies showed signaling by epinephrine/epinephrine receptor in T cells is involved in autoimmune diseases. Nevertheless, the production of epinephrine by T cells and its pathogenic function in T cells are not well investigated. Our results show that phenylethanol N-methyltransferase (PNMT), a rate-limiting enzyme of epinephrine synthesis, is specifically expressed in vitro in differentiated TH17 cells and in tissue-resident TH17 cells. Indeed, expression levels of enzymes involved in epinephrine production are higher in TH17 cells from animals after EAE induction. The induction of PNMT was not observed in other effector T cell subsets or regulatory T cells. Epinephrine producing TH17 cells exhibit co-expression of GM-CSF, suggesting they are pathogenic TH17 cells. To delineate the function of epinephrine-production in TH17 cells, we generated a TH17-specific knockout of tyrosine hydroxylase (Th) by breeding a Th-flox and a ROR-gt-CRE mouse (Th-CKO). Th-CKO mice are developmentally normal with an equivalent T lymphocyte number in peripheral lymphoid organs. Th-CKO mice also show an equivalent number of TH17 cells in vivo and following in vitro differentiation. To test whether epinephrine-producing TH17 cells are key for breaching the BBB, migration of T cells through mouse brain endothelial cells was investigated in vitro. Both epi+ wild-type and epi- TH17 cells migrate through an endothelial cell barrier. Mice were immunized with MOG peptide to induce experimental autoimmune encephalitis (EAE) and disease progression was monitored. Although there is a reduced infiltration of CD4+ T cells in Th-CKO mice, no difference in clinical score was observed between Th-CKO and wild-type control mice. Increased neutrophils were observed in the central nervous system of Th-CKO mice, suggesting an alternative pathway to EAE progression in the absence of TH17 derived epinephrine.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Epinefrina/biossíntese , Células Th17/imunologia , Células Th17/metabolismo , Animais , Biomarcadores , Barreira Hematoencefálica/metabolismo , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Knockout , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Migração Transendotelial e Transepitelial/imunologia
20.
Front Immunol ; 12: 584538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679735

RESUMO

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Cardiopatias/imunologia , Memória Imunológica/imunologia , Miocárdio/imunologia , Envelhecimento/genética , Animais , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Expressão Gênica/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Cadeias HLA-DRB1/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Memória Imunológica/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , RNA-Seq/métodos , Transplante Heterólogo
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