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1.
J Biol Chem ; 297(3): 101097, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418432

RESUMO

Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) plays context-specific roles in multiple receptor-mediated signaling pathways in different cell types. Mice lacking TRAF3 in T cells display defective T-cell-mediated immune responses to immunization and infection and demonstrate defective early signaling via the TCR complex. However, the role of TRAF3 in the function of GITR/TNFRSF18, an important costimulatory member of the TNFR superfamily, is unclear. Here we investigated the impact of T cell TRAF3 status on both GITR expression and activation of specific kinases in the GITR signaling pathway in T cells. Our results indicate that TRAF3 negatively regulates GITR functions in several ways. First, expression of GITR protein was elevated in TRAF3-deficient T cells, resulting from both transcriptional and posttranslational regulation that led to greater GITR transcript levels, as well as enhanced GITR protein stability. TRAF3 associated with T cell GITR in a manner dependent upon GITR ligation. TRAF3 also inhibited several events of the GITR mediated early signaling cascade, in a manner independent of recruitment of phosphatases, a mechanism by which TRAF3 inhibits signaling through several other cytokine receptors. These results add new information to our understanding of GITR signaling and function in T cells, which is relevant to the potential use of GITR to enhance immune therapies.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Animais , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/fisiologia , Interleucina-2/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Fator 3 Associado a Receptor de TNF/fisiologia
2.
Front Immunol ; 12: 656366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149695

RESUMO

Amphioxus (e.g., Branchiostoma belcheri, Bb) has recently emerged as a new model for studying the origin and evolution of vertebrate immunity. Mammalian lymphocyte-specific tyrosine kinase (Lck) plays crucial roles in T cell activation, differentiation and homeostasis, and is reported to phosphorylate both the ITIM and ITSM of PD-1 to induce the recruitment of phosphatases and thus the inhibitory function of PD-1. Here, we identified and cloned the amphioxus homolog of human Lck. By generating and using an antibody against BbLck, we found that BbLck is expressed in the amphioxus gut and gill. Through overexpression of BbLck in Jurkat T cells, we found that upon TCR stimulation, BbLck was subjected to tyrosine phosphorylation and could partially rescue Lck-dependent tyrosine phosphorylation in Lck-knockdown T cells. Mass spectrometric analysis of BbLck immunoprecipitates from immunostimulants-treated amphioxus, revealed a BbLck-associated membrane-bound receptor LRR (BbLcLRR). By overexpressing BbLcLRR in Jurkat T cells, we demonstrated that BbLcLRR was tyrosine phosphorylated upon TCR stimulation, which was inhibited by Lck knockdown and was rescued by overexpression of BbLck. By mutating single tyrosine to phenylalanine (Y-F), we identified three tyrosine residues (Y539, Y655, and Y690) (3Y) of BbLcLRR as the major Lck phosphorylation sites. Reporter gene assays showed that overexpression of BbLcLRR but not the BbLcLRR-3YF mutant inhibited TCR-induced NF-κB activation. In Lck-knockdown T cells, the decline of TCR-induced IL-2 production was reversed by overexpression of BbLck, and this reversion was inhibited by co-expression of BbLcLRR but not the BbLcLRR-3YF mutant. Sequence analysis showed that the three tyrosine-containing sequences were conserved with the tyrosine-based inhibition motifs (ITIMs) or ITIM-like motifs. And TCR stimulation induced the association of BbLcLRR with tyrosine phosphatases SHIP1 and to a lesser extent with SHP1/2. Moreover, overexpression of wild-type BbLcLRR but not its 3YF mutant inhibited TCR-induced tyrosine phosphorylation of multiple signaling proteins probably via recruiting SHIP1. Thus, we identified a novel immunoreceptor BbLcLRR, which is phosphorylated by Lck and then exerts a phosphorylation-dependent inhibitory role in TCR-mediated T-cell activation, implying a mechanism for the maintenance of self-tolerance and homeostasis of amphioxus immune system and the evolutionary conservatism of Lck-regulated inhibitory receptor pathway.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Anfioxos/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Animais , Biomarcadores , Clonagem Molecular , Receptores Coestimuladores e Inibidores de Linfócitos T/genética , Bases de Dados Genéticas , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Interleucina-2/biossíntese , Células Jurkat , Anfioxos/genética , Ativação Linfocitária , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Fosforilação , Coelhos , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Sequência de DNA , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
3.
Front Immunol ; 12: 597761, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717075

RESUMO

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.


Assuntos
Suscetibilidade a Doenças/imunologia , Hipersensibilidade a Drogas/etiologia , Imunomodulação , Animais , Biomarcadores , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Diagnóstico Diferencial , Hipersensibilidade a Drogas/diagnóstico , Regulação da Expressão Gênica , Humanos , Índice de Gravidade de Doença , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Eur J Immunol ; 51(2): 331-341, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32920841

RESUMO

Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte activation gene-3 (LAG-3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG-3 are still not understood. Using surface plasmon resonance combined with a novel bead-based assay (AlphaScreenTM ), we demonstrate that LAG-3 can directly and specifically interact with intact human leukocyte antigen class II (HLA-II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG-3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG-3+ cells with pHLA-II-multimers. These data provide new insights into the mechanism by which LAG-3 initiates T cell inhibition.


Assuntos
Antígenos CD/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Antígenos HLA/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Antígenos CD4/imunologia , Linhagem Celular Tumoral , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Células Jurkat , Neoplasias/imunologia , Proteína do Gene 3 de Ativação de Linfócitos
5.
Semin Immunol ; 49: 101436, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-33288379

RESUMO

T cells play a critical role in promoting tumor regression in both experimental models and humans. Yet, T cells that are chronically exposed to tumor antigen during cancer progression can become dysfunctional/exhausted and fail to induce tumor destruction. Such tumor-induced T cell dysfunction may occur via multiple mechanisms. In particular, immune checkpoint inhibitory receptors that are upregulated by tumor-infiltrating lymphocytes in many cancers limit T cell survival and function. Overcoming this inhibitory receptor-mediated T cell dysfunction has been a central focus of recent developments in cancer immunotherapy. Immunotherapies targeting inhibitory receptor pathways such as programmed cell death 1 (PD-1)/programmed death ligand 1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), alone or in combination, confer significant clinical benefits in multiple tumor types. However, many patients with cancer do not respond to immune checkpoint blockade, and dual PD-1/CTLA-4 blockade may cause serious adverse events, which limits its indications. Targeting novel non-redundant inhibitory receptor pathways contributing to tumor-induced T cell dysfunction in the tumor microenvironment may prove efficacious and non-toxic. This review presents preclinical and clinical findings supporting the roles of two key pathways-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domain (TIGIT)/CD226/CD96/CD112R-in cancer immunotherapy.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biomarcadores Tumorais , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais , Subpopulações de Linfócitos T/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
6.
Front Immunol ; 11: 592329, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193438

RESUMO

Among the areas of most impactful recent progress in immunology is the discovery of inhibitory receptors and the subsequent translation of this knowledge to the clinic. Although the original and canonical member of this family is FcγRIIB, more recent studies defined PD1 as an inhibitory receptor that constrains T cell immunity to tumors. These studies led to development of "checkpoint blockade" immunotherapies (CBT) for cancers in which PD1 interactions with its ligand are blocked. Unfortunately, although very effective in some patients, only a small proportion respond to this therapy. This suggests that additional as yet undescribed inhibitory receptors exist, which could be exploited. Here, we describe a new platform, termed inhibitory receptor trap (IRT), for discovery of members of this family. The approach takes advantage of the fact that many of the known inhibitory receptors mediate signaling by phospho-immunoreceptor tyrosine-based inhibition motif (ITIM) mediated recruitment of Src Homology 2 (SH2) domain-containing phosphatases including the SH2 domain-containing inositol phosphatase SHIP1 encoded by the INPP5D gene and the SH2 domain-containing phosphotyrosine phosphatases SHP1 and SHP2 encoded by the PTPN6 and PTPN11 genes respectively. Here, we describe the IRT discovery platform in which the SH2 domains of inhibitory phosphatases are used for affinity-based isolation and subsequent identification of candidate effectors via immunoblotting and high sensitivity liquid chromatography-mass spectrometry. These receptors may represent alternative targets that can be exploited for improved CBT. Salient observations from these studies include the following: SH2 domains derived from the respective phosphatases bind distinct sets of candidates from different cell types. Thus, cells of different identity and different activation states express partially distinct repertoires of up and downstream phosphatase effectors. Phosphorylated PD1 binds not only SHP2 but also SHIP1, thus the latter may be important in its inhibitory function. B cell antigen receptor signaling leads predominantly to CD79 mono-phosphorylation as indicated by much greater binding to LynSH2 than Syk(SH2)2. This balance of ITAM mono- versus bi-phosphorylation likely tunes signaling by varying activation of inhibitory (Lyn) and stimulatory (Syk) pathways.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Antígenos CD/metabolismo , Receptores Coestimuladores e Inibidores de Linfócitos T/química , Feminino , Camundongos , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Domínios de Homologia de src
7.
Front Immunol ; 11: 2188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072082

RESUMO

The understanding of protective immunity during HIV infection remains elusive. Here we showed that CD160 defines a polyfunctional and proliferative CD8+ T cell subset with a protective role during chronic HIV-1 infection. CD160+ CD8+ T cells derived from HIV+ patients correlated with slow progressions both in a cross-sectional study and in a 60-month longitudinal cohort, displaying enhanced cytotoxicity and proliferative capacity in response to HIV Gag stimulation; triggering CD160 promoted their functionalities through MEK-ERK and PI3K-AKT pathways. These observations were corroborated by studying chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The genetic ablation of CD160 severely impaired LCMV-specific CD8+ T cell functionalities and thereby resulted in loss of virus control. Interestingly, transcriptional profiling showed multiple costimulatory and survival pathways likely to be involved in CD160+ T cell development. Our data demonstrated that CD160 acts as a costimulatory molecule positively regulating CD8+ T cells during chronic viral infections, thus representing a potential target for immune intervention.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Infecções por HIV/imunologia , Coriomeningite Linfocítica/imunologia , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Doença Crônica , Progressão da Doença , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/imunologia , Produtos do Gene gag/fisiologia , HIV-1 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Imunológicos/deficiência , Subpopulações de Linfócitos T/transplante , Transcriptoma
8.
Int Immunopharmacol ; 89(Pt B): 107097, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33091814

RESUMO

Although anti-PD-1/L1 and anti-CTLA-4 antibodies, the validated immune checkpoint blockades, can elicit durable long-lasting antitumor immunity and improve the clinical outcomes of melanoma treatment, there are still a fraction of patients who did not receive therapeutic benefits as expected. In addition to findings of blocking the co-inhibitory pathways, the preclinical and clinical evidence suggests that triggering the co-stimulatory pathways through agonists such as CD137, OX40, CD40, GITR and CD27 may be a rational next step for melanoma therapy. In this review, we discuss the progress of studies on these co-stimulatory molecules in terms of their promising therapeutic effects and underlying antitumor mechanisms, and provide a review of the possible combinations that orchestrate the interplay of co-stimulatory agonistic mAbs and other therapies for treating melanoma, including inhibitory immune checkpoint mAbs, adoptive T cell therapy, chemotherapy and radiotherapy. We also briefly present the limitations and challenges involved in these co-stimulatory agonistic mAb-based combination strategies for melanoma patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Terapia Combinada/métodos , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Humanos , Receptores de Antígenos de Linfócitos T/metabolismo
10.
Front Immunol ; 11: 2025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973809

RESUMO

During pregnancy, various immune effectors and molecules participating in the immune-microenvironment establish specific maternal tolerance toward the semi-allogeneic fetus. Activated maternal immune effectors by the trophoblast antigens, such as T helper (Th), T cytotoxic (Tc), T regulatory (Treg), and B cells, are involved in the regulation of adaptive immunity. Recognition of active signal through the T cell receptors stimulate the differentiation of naive CD3+CD4+ T cells into specific T cell subsets, such as Th1, Th2, Th9, Th17, Th22, and follicular Th cells (Tfh). Each of these subsets has a significant and distinct role in human pregnancy. Th1 immunity, characterized by immune-inflammatory responses, becomes dominant during the peri-implantation period, and the "controlled" Th1 immunity benefits the invading trophoblasts rather than harm. Quickly after the placental implantation, the early inflammatory Th1 immunity is shifted to the Th2 anti-inflammatory immune responses. The predominant Th2 immunity, which overrules the Th1 immunity at the placental implantation site, protects a fetus by balancing Th1 immunity and accommodate fetal and placental development. Moreover, Treg and Th9 cells regulate local inflammatory immune responses, potentially detrimental to the fetus. Th17 cells induce protective immunity against extracellular microbes during pregnancy. However, excessive Th17 immunity may induce uncontrolled neutrophil infiltration at the maternal-fetal interface. Other Th cell subsets such as Tfh cells, also contribute to pregnancy by setting up favorable humoral immunity during pregnancy. However, dysregulation of Th cell immunity during pregnancy may result in obstetrical complications, such as recurrent pregnancy losses (RPL) and preeclampsia (PE). With this review, we intend to deliver a comprehensive overview of CD4+ Th cell subsets, including Th1, Th2, Th9, Th17, Th22, and Tfh cells, in human pregnancy by reviewing their roles in normal and pathological pregnancies.


Assuntos
Aborto Habitual/etiologia , Aborto Habitual/metabolismo , Células T Auxiliares Foliculares/imunologia , Subpopulações de Linfócitos T/imunologia , Aborto Habitual/terapia , Sobrevivência Celular/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Implantação do Embrião/imunologia , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Homeostase , Humanos , Tolerância Imunológica , Imunidade Celular , Imunidade Humoral , Imunomodulação , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Placenta/metabolismo , Gravidez , Células T Auxiliares Foliculares/metabolismo , Subpopulações de Linfócitos T/metabolismo , Trofoblastos/imunologia , Trofoblastos/metabolismo
11.
Minerva Pediatr ; 72(5): 393-407, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32960006

RESUMO

Inborn errors of immunity are diseases of the immune system resulting from mutations that alter the expression of encoded proteins or molecules. Total updated number of these disorders is currently 406, with 430 different identified gene defects involved. Studies of the underlying mechanisms have contributed in better understanding the pathophysiology of the diseases, but also the complexity of the biology of innate and adaptive immune system and its interaction with microbes. In this review we present and briefly discuss Inborn Errors of Immunity caused by defects in genes encoding for receptors and protein of cellular membrane, including cytokine receptors, T cell antigen receptor (TCR) complex, cellular surface receptors or receptors signaling causing predominantly antibody deficiencies, co-stimulatory receptors and others. These alterations impact many biological processes of immune-system cells, including development, proliferation, activation and down-regulation of the immunological response, and result in a variety of diseases that present with distinct clinical features or with overlapping signs and symptoms.


Assuntos
Doenças do Sistema Imunitário/genética , Proteínas de Membrana/genética , Mutação , Receptores Coestimuladores e Inibidores de Linfócitos T/genética , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Doenças do Sistema Imunitário/imunologia , Imunidade Celular/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Superfície Celular/genética , Receptores de Citocinas/genética
12.
Transpl Immunol ; 63: 101330, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32896615

RESUMO

Innate immune reactions are believed to be associated with ischemia/reperfusion injury (IRI), and IRI might be treatable by expanding regulatory T cells (Tregs), which can suppress the excessive responses of the immune system. Organ IRI is known to be closely involved in the expression of costimulatory molecules. The present study aimed to assess whether Tregs endogenously expanded by the administration of trichostatin A (TsA), a histone deacetylase inhibitor, could reduce renal IRI and to clarify their association with the expression of costimulatory molecules in a murine model. In this study, the wild-type mice used for an IRI model were randomly divided into the following four treatment groups: TsA group, DMSO group (control), DMSO+PC61 group, and TsA + PC61 group. Renal injury in the early phase after IRI was ameliorated in the TsA group (increased Tregs) when compared with the other groups. After renal IRI, both the mRNA and the protein levels of anti-inflammatory cytokines, IL-10 and TGF-ß in the kidney and spleen were significantly higher in the TsA group than in the other groups, whereas the IL-6 levels were significantly lower in the TsA group than in the other groups. These results were offset by the administration of PC61, supporting that the renoprotective effect of TsA in this study is Treg dependent. mRNA expression levels of CD80, CD86, and ICAM-1 were lower in the TsA group, consistent with Treg control of injury through costimulatory molecules. Our findings suggest that endogenously expanded Tregs coordinate postischemic immune responses and decrease the expression of costimulatory molecules after renal IRI, and thus, they might ameliorate renal IRI. TsA administration for expanding Tregs is a promising therapeutic strategy for renal IRI.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Rim/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Proliferação de Células , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Rim/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos
13.
Int J Mol Sci ; 21(18)2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32899567

RESUMO

Human retinal pigment epithelial (RPE) cells derived from induced pluripotent stem (iPS) cells have immunosuppressive properties. However, RPE cells are also known as immunogenic cells, and they have major histocompatibility complex expression and produce inflammatory proteins, and thus experience immune rejection after transplantation. In this study, to confirm the immunological properties of IPS-RPE cells, we examined whether human RPE cells derived from iPS cells could suppress or stimulate inflammatory T cells from uveitis patients via costimulatory signals. We established T cells from patients with active uveitis as target cells and used iPS-RPE cells as effector cells. As a result, cultured iPS-RPE cells inhibited cell proliferation and the production of IFN-γ by activated uveitis CD4+ T cells, especially Th1-type T cells. In contrast, iPS-RPE cells stimulated T cells of uveitis patients. The iPS-RPE cells constitutively expressed B7-H1/CD274 and B7-DC/CD273, and suppressed the activation of T cells via the PD-1 receptor. iPS-RPE expressed these negative costimulatory molecules, especially when RPE cells were pretreated with recombinant IFN-γ. In addition, iPS-RPE cells also expressed B7-H3/CD276 costimulatory molecules and activated uveitis T cells through the B7-H3-TLT-2 receptor. Thus, cultured iPS-derived retinal cells can suppress or activate inflammatory T cells in vitro through costimulatory interactions.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Epitélio Pigmentado da Retina/metabolismo , Linfócitos T/fisiologia , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Células Epiteliais/metabolismo , Citometria de Fluxo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Epitélio Pigmentado da Retina/imunologia , Epitélio Pigmentado da Retina/fisiologia , Pigmentos da Retina/metabolismo , Uveíte/imunologia , Uveíte/metabolismo
15.
Mucosal Immunol ; 13(5): 721-731, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32415229

RESUMO

Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential.


Assuntos
Imunidade Inata , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Antígenos/imunologia , Biomarcadores , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Humanos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo
16.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-32345776

RESUMO

The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on nai¨ve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/fisiologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Linfócitos T/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD28/química , Antígenos CD28/metabolismo , Antígeno CTLA-4/química , Antígeno CTLA-4/metabolismo , Receptores Coestimuladores e Inibidores de Linfócitos T/química , Receptores Coestimuladores e Inibidores de Linfócitos T/genética , Humanos , Ativação Linfocitária , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia
17.
Nat Rev Immunol ; 20(11): 680-693, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32269380

RESUMO

Regulatory T (Treg) cells constitute a dynamic population that is essential for controlling immune responses in health and disease. Defects in Treg cell function and decreases in Treg cell numbers have been observed in patients with autoimmunity and the opposite effects on Treg cells occur in cancer settings. Current research on new therapies for these diseases is focused on modulating Treg cell function to increase or decrease suppressive activity in autoimmunity and cancer, respectively. In this regard, several co-inhibitory receptors that are preferentially expressed by Treg cells under homeostatic conditions have recently been shown to control Treg cell function and stability in different disease settings. These receptors could be amenable to therapeutic targeting aimed at modulating Treg cell function and plasticity. This Review summarizes recent data regarding the role of co-inhibitory molecules in the control of Treg cell function and stability, with a focus on their roles and potential therapeutic use in autoimmunity and cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Receptores Coestimuladores e Inibidores de Linfócitos T/efeitos dos fármacos , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos
18.
Cancer Sci ; 111(7): 2223-2233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32324315

RESUMO

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vß11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.


Assuntos
Antígenos CD1d/metabolismo , Leucemia/imunologia , Leucemia/metabolismo , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Animais , Antígenos CD1d/genética , Biomarcadores , Degranulação Celular , Linhagem Celular Tumoral , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Edição de Genes , Xenoenxertos , Humanos , Imunofenotipagem , Leucemia/genética , Leucemia/patologia , Ativação Linfocitária/genética , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Desencadeadores da Citotoxicidade Natural/metabolismo
19.
Sci Adv ; 6(8): eaaz0374, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128419

RESUMO

Mucosal-associated invariant T (MAIT) cells in HIV-1-infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1-infected subjects were highly activated with the up-regulation of interferon (IFN)-stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti-Mycobacterium tuberculosis responses of MAIT cells from HIV-1-infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti-IFN-I/IL-10 strategies against bacterial coinfections in HIV-1-infected patients.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Interferon Tipo I/metabolismo , Interleucina-10/biossíntese , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/virologia , Terapia Antirretroviral de Alta Atividade , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/etiologia , Feminino , Infecções por HIV/complicações , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária , Masculino , Transdução de Sinais
20.
Cancer Immunol Immunother ; 69(5): 759-769, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32052079

RESUMO

BACKGROUND: Resistance to immune checkpoint blockade and targeted therapy in melanoma patients is currently one of the major clinical challenges. With the approval of talimogene laherparepvec (T-VEC), oncolytic viruses are now in clinical practice for locally advanced or non-resectable melanoma. Here, we describe the usage of T-VEC in stage IVM1b-M1c melanoma patients, who achieved complete remission or stable disease upon systemic treatment but suffered from a loco-regional recurrence. To our knowledge, there are no case reports so far describing T-VEC as a means to overcome acquired resistance to immune checkpoint blockade or targeted therapy. METHODS: All melanoma patients in our department treated with T-VEC in the period of 2016-2018 were evaluated retrospectively. Data on clinicopathological characteristics, treatment response, and toxicity were analyzed. RESULTS: Fourteen melanoma patients were treated with T-VEC in our center. Six patients (43%) received T-VEC first-line. In eight patients (57%), T-VEC followed a prior systemic therapy. Three patients with M1b stage and one patient with M1c stage melanoma were treated with T-VEC. These patients suffered from loco-regional progress, whilst distant metastases had regressed during prior systemic treatment. 64% of patients showed a benefit from therapy with T-VEC. The durable response rate was 36%. CONCLUSION: T-VEC represents an effective and tolerable treatment option. This is true not only for loco-regionally advanced melanoma patients, but also for patients with stable or regressive systemic metastases who develop loco-regionally acquired resistance upon treatment with immune checkpoint blockade or targeted therapy. A sensible selection of suitable patients seems to be crucial.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Produtos Biológicos/administração & dosagem , Imunoterapia/métodos , Melanoma/terapia , Terapia Viral Oncolítica/métodos , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Seguimentos , Herpesvirus Humano 1 , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
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