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1.
Nat Commun ; 12(1): 4882, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385466

RESUMO

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment-induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and have more than a 90% probability to develop chronic hepatitis C (CHC). Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV. Here we describe an effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells are significantly weaker activators of HCV specific CD8+ T cells than unstressed cells. This is not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses are restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impairs HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4-HCV paradox.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Células A549 , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Linhagem Celular Tumoral , Regulação da Expressão Gênica/imunologia , Genótipo , Células Hep G2 , Hepacivirus/genética , Hepacivirus/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucinas/genética , Interleucinas/metabolismo
2.
J Immunol ; 207(4): 1150-1164, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34341167

RESUMO

CARD11 is a multidomain scaffold protein required for normal activation of NF-κB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-κB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.


Assuntos
Linfócitos B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Imunoglobulina E/imunologia , Células Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Alelos , Animais , Heterozigoto , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Front Immunol ; 12: 697840, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394090

RESUMO

Monocytes are antigen-presenting cells (APCs) that play diverse roles in promoting or regulating inflammatory responses, but their role in T cell stimulation is not well defined. In inflammatory conditions, monocytes frequently show increased expression of CD169/Siglec-1, a type-I interferon (IFN-I)-regulated protein. However, little is known about the phenotype and function of these CD169+ monocytes. Here, we have investigated the phenotype of human CD169+ monocytes in different diseases, their capacity to activate CD8+ T cells, and the potential for a targeted-vaccination approach. Using spectral flow cytometry, we detected CD169 expression by CD14+ CD16- classical and CD14+ CD16+ intermediate monocytes and unbiased analysis showed that they were distinct from dendritic cells, including the recently described CD14-expressing DC3. CD169+ monocytes expressed higher levels of co-stimulatory and HLA molecules, suggesting an increased activation state. IFNα treatment highly upregulated CD169 expression on CD14+ monocytes and boosted their capacity to cross-present antigen to CD8+ T cells. Furthermore, we observed CD169+ monocytes in virally-infected patients, including in the blood and bronchoalveolar lavage fluid of COVID-19 patients, as well as in the blood of patients with different types of cancers. Finally, we evaluated two CD169-targeting nanovaccine platforms, antibody-based and liposome-based, and we showed that CD169+ monocytes efficiently presented tumor-associated peptides gp100 and WT1 to antigen-specific CD8+ T cells. In conclusion, our data indicate that CD169+ monocytes are activated monocytes with enhanced CD8+ T cell stimulatory capacity and that they emerge as an interesting target in nanovaccine strategies, because of their presence in health and different diseases.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Monócitos/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , COVID-19/imunologia , Carcinoma Ductal Pancreático/imunologia , Células Cultivadas , Citometria de Fluxo , Humanos , Influenza Humana/imunologia , Interferon-alfa/farmacologia , Receptores de Lipopolissacarídeos/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pancreáticas/imunologia , SARS-CoV-2/imunologia
4.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426690

RESUMO

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Fatores de Transcrição Forkhead/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Homeostase/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Resposta Inflamatória Sistêmica/patologia
5.
Sci Adv ; 7(34)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407944

RESUMO

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.


Assuntos
COVID-19/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Melanoma/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Idoso , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Melanoma/complicações , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia
6.
J Immunol ; 207(4): 1009-1017, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321228

RESUMO

The human CD8+ T cell clone 6C5 has previously been shown to recognize the tert-butyl-modified Bax161-170 peptide LLSY(3-tBu)FGTPT presented by HLA-A*02:01. This nonnatural epitope was likely created as a by-product of fluorenylmethoxycarbonyl protecting group peptide synthesis and bound poorly to HLA-A*02:01. In this study, we used a systematic approach to identify and characterize natural ligands for the 6C5 TCR. Functional analyses revealed that 6C5 T cells only recognized the LLSYFGTPT peptide when tBu was added to the tyrosine residue and did not recognize the LLSYFGTPT peptide modified with larger (di-tBu) or smaller chemical groups (Me). Combinatorial peptide library screening further showed that 6C5 T cells recognized a series of self-derived peptides with dissimilar amino acid sequences to LLSY(3-tBu)FGTPT. Structural studies of LLSY(3-tBu)FGTPT and two other activating nonamers (IIGWMWIPV and LLGWVFAQV) in complex with HLA-A*02:01 demonstrated similar overall peptide conformations and highlighted the importance of the position (P) 4 residue for T cell recognition, particularly the capacity of the bulky amino acid tryptophan to substitute for the tBu-modified tyrosine residue in conjunction with other changes at P5 and P6. Collectively, these results indicated that chemical modifications directly altered the immunogenicity of a synthetic peptide via molecular mimicry, leading to the inadvertent activation of a T cell clone with unexpected and potentially autoreactive specificities.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Fragmentos de Peptídeos/imunologia , Peptídeos/imunologia , Sequência de Aminoácidos , Apresentação do Antígeno/imunologia , Células Cultivadas , Epitopos de Linfócito T/imunologia , Humanos , Ligantes , Biblioteca de Peptídeos
7.
J Immunol ; 207(4): 1194-1199, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34330751

RESUMO

T cell lymphomas arise in mice that constitutively express a single TCR in the absence of NK cells. Upon TCR engagement these lymphomas are able to corrupt tumor surveillance by decreasing NK cell numbers. In this study, we investigate the outcome of interactions between these T cell lymphomas and dendritic cells. Bone marrow-derived dendritic cells mediated effective killing of T cell lymphomas after activation with IFN-γ and TLR ligands in culture. This cytotoxicity was independent of MHC compatibility. Cell lysis was reduced by the presence of the peroxynitrite inhibitors FeTTPS and L-NMMA, whereas inhibitors of apoptosis, death receptors, and degranulation were without effect, suggesting NO metabolites as the main mediators. When injected together with GM-CSF and R848 into lymphoma-bearing mice, in vitro-expanded bone marrow-derived dendritic cells caused significant survival increases. These data show that dendritic cell adaptive immunotherapy can be used as treatment against T cell lymphomas in mice.


Assuntos
Citotoxicidade Imunológica/imunologia , Células Dendríticas/imunologia , Linfoma de Células T/imunologia , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
8.
J Immunol ; 207(4): 1018-1032, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34330755

RESUMO

Germinal center reactions are established during a thymus-dependent immune response. Germinal center (GC) B cells are rapidly proliferating and undergo somatic hypermutation in Ab genes. This results in the production of high-affinity Abs and establishment of long-lived memory cells. GC B cells show lower BCR-induced signaling when compared with naive B cells, but the functional relevance is not clear. CD22 is a member of the Siglec family and functions as an inhibitory coreceptor on B cells. Interestingly, GC B cells downregulate sialic acid forms that serve as high-affinity ligands for CD22, indicating a role for CD22 ligand binding during GC responses. We studied the role of CD22 in the GC with mixed bone marrow chimeric mice and found a disadvantage of CD22-/- GC B cells during the GC reaction. Mechanistic investigations ruled out defects in dark zone/light zone distribution and affinity maturation. Rather, an increased rate of apoptosis in CD22-/- GC B cells was responsible for the disadvantage, also leading to a lower GC output in plasma cells and memory B cells. CD22-/- GC B cells showed a clearly increased calcium response upon BCR stimulation, which was almost absent in wild-type GC B cells. We conclude that the differential expression of the low-affinity cis CD22 ligands in the GC normally results in a strong attenuation of BCR signaling in GC B cells, probably due to higher CD22-BCR interactions. Therefore, attenuation of BCR signaling by CD22 is involved in GC output and B cell fate.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Memória Imunológica/imunologia , Plasmócitos/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/imunologia , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia
9.
Nat Immunol ; 22(8): 1042-1051, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267375

RESUMO

Pathogens and vaccines that produce persisting antigens can generate expanded pools of effector memory CD8+ T cells, described as memory inflation. While properties of inflating memory CD8+ T cells have been characterized, the specific cell types and tissue factors responsible for their maintenance remain elusive. Here, we show that clinically applied adenovirus vectors preferentially target fibroblastic stromal cells in cultured human tissues. Moreover, we used cell-type-specific antigen targeting to define critical cells and molecules that sustain long-term antigen presentation and T cell activity after adenovirus vector immunization in mice. While antigen targeting to myeloid cells was insufficient to activate antigen-specific CD8+ T cells, genetic activation of antigen expression in Ccl19-cre-expressing fibroblastic stromal cells induced inflating CD8+ T cells. Local ablation of vector-targeted cells revealed that lung fibroblasts support the protective function and metabolic fitness of inflating memory CD8+ T cells in an interleukin (IL)-33-dependent manner. Collectively, these data define a critical fibroblastic niche that underpins robust protective immunity operating in a clinically important vaccine platform.


Assuntos
Adenoviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-33/imunologia , Ativação Linfocitária/imunologia , Células Estromais/imunologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Quimiocina CCL19/metabolismo , Quimera/genética , Epitopos de Linfócito T/imunologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/imunologia , Humanos , Pulmão/citologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vacinação
10.
J Immunol ; 207(4): 1065-1077, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321229

RESUMO

CNS tuberculosis (CNSTB) is the most severe manifestation of extrapulmonary tuberculosis infection, but the mechanism of how mycobacteria cross the blood-brain barrier (BBB) is not well understood. In this study, we report a novel murine in vitro BBB model combining primary brain endothelial cells, Mycobacterium bovis bacillus Calmette-Guérin-infected dendritic cells (DCs), PBMCs, and bacterial Ag-specific CD4+ T cells. We show that mycobacterial infection limits DC mobility and also induces cellular cluster formation that has a similar composition to pulmonary mycobacterial granulomas. Within the clusters, infection from DCs disseminates to the recruited monocytes, promoting bacterial expansion. Mycobacterium-induced in vitro granulomas have been described previously, but this report shows that they can form on brain endothelial cell monolayers. Cellular cluster formation leads to cluster-associated damage of the endothelial cell monolayer defined by mitochondrial stress, disorganization of the tight junction proteins ZO-1 and claudin-5, upregulation of the adhesion molecules VCAM-1 and ICAM-1, and increased transmigration of bacteria-infected cells across the BBB. TNF-α inhibition reduces cluster formation on brain endothelial cells and mitigates cluster-associated damage. These data describe a model of bacterial dissemination across the BBB shedding light on a mechanism that might contribute to CNS tuberculosis infection and facilitate treatments.


Assuntos
Barreira Hematoencefálica/imunologia , Células Dendríticas/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Granuloma/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/imunologia
11.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299173

RESUMO

Diabetic nephropathy (DN) is one of the most significant microvascular complications in diabetic patients. DN is the leading cause of end-stage renal disease, accounting for approximately 50% of incident cases. The current treatment options, such as optimal control of hyperglycemia and elevated blood pressure, are insufficient to prevent its progression. DN has been considered as a nonimmune, metabolic, or hemodynamic glomerular disease initiated by hyperglycemia. However, recent studies suggest that DN is an inflammatory disease, and immune cells related with innate and adaptive immunity, such as macrophage and T cells, might be involved in its development and progression. Although it has been revealed that kidney dendritic cells (DCs) accumulation in the renal tissue of human and animal models of DN require activated T cells in the kidney disease, little is known about the function of DCs in DN. In this review, we describe kidney DCs and their subsets, and the role in the pathogenesis of DN. We also suggest how to improve the kidney outcomes by modulating kidney DCs optimally in the patients with DN.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Ativação Linfocitária/imunologia , Animais , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Humanos
12.
J Immunol ; 207(4): 1099-1111, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34312258

RESUMO

Understanding the function of SARS-CoV-2 Ag-specific T cells is crucial for the monitoring of antiviral immunity and vaccine design. Currently, both impaired and robust T cell immunity is described in COVID-19 patients. In this study, we explored and compared the effector functions of SARS-CoV-2-reactive T cells expressing coinhibitory receptors and examine the immunogenicity of SARS-CoV-2 S, M, and N peptide pools in regard to specific effector T cell responses, Th1/Th2/Th17, in COVID-19 patients. Analyzing a cohort of 108 COVID-19 patients with mild, moderate, and severe disease, we observed that coinhibitory receptors (e.g., PD-1, CTLA-4, TIM-3, VISTA, CD39, CD160, 2B4, TIGIT, Gal-9, and NKG2A) were upregulated on both CD4+ and CD8+ T cells. Importantly, the expression of coinhibitory receptors on T cells recognizing SARS-CoV-2 peptide pools (M/N/S) was associated with increased frequencies of cytokine-producing T cells. Thus, our data refute the concept of pathological T cell exhaustion in COVID-19 patients. Despite interindividual variations in the T cell response to viral peptide pools, a Th2 phenotype was associated with asymptomatic and milder disease, whereas a robust Th17 was associated with severe disease, which may potentiate the hyperinflammatory response in patients admitted to the Intensive Care Unit. Our data demonstrate that T cells may either play a protective or detrimental role in COVID-19 patients. This finding could have important implications for immune correlates of protection, diagnostic, and prophylaxis with respect to COVID-19 management.


Assuntos
COVID-19/imunologia , SARS-CoV-2/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Idoso , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Proteínas da Matriz Viral/imunologia
13.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281195

RESUMO

Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.


Assuntos
Metilação de DNA , Linfócitos T Reguladores/fisiologia , Antígeno CTLA-4/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Expressão Gênica , Regulação da Expressão Gênica , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Humanos , Fator de Transcrição Ikaros/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
14.
Mol Immunol ; 137: 221-227, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34284214

RESUMO

Natural Killer (NK) cells are considered the first line of defense against viral infections and tumors. Several factors affect NK cytotoxic activity rendering it dysfunctional and thereby impeding the ability to scavenge abnormal cells as a part of immune escaping mechanisms induced by different types of cancers. NK cells play a crucial role augmenting the activity of various types of anticancer mAb since dysfunctional NK cells are the main reason for the low response to these therapies. To this light, we examined the phenotypic characters of the circulating NK cells isolated from HCC patients compared to healthy controls. Then, dysfunctional NK cells, from HCC patients, were reactivated with cytokines cocktail and their cytotoxic activity with the anti-EGFR mAb "cetuximab" was investigated. This showed a downregulation of patients NK cells activating receptors (NKP30, NKP46, NKG2D and CD16) as well as CD56 and up-regulation of NKG2A inhibitory receptor. We also reported an increase in aberrant CD56- NK cells subset in peripheral blood of HCC patients compared to healthy controls. Thus, confirming the dysfunctionality of peripheral NK cells isolated from HCC patients. Cytokines re-activation of those NK cells lead to upregulation of NK activating receptors and downregulation of inhibitory receptor. Moreover, the percentage of aberrant CD56- NK cells subset was reduced. Here, we proved that advanced HCC patients have an increased percentage of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for the low cytotoxicity noticed in those patients. A significant improvement in the cytotoxicity against HCC was noticed upon using reactivated NK cells combined with cetuximab. Therefore, this study highlights the potential recruitment of NK immune cells along with cetuximab to enhance cytotoxicity against HCC.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Cetuximab/uso terapêutico , Citocinas/farmacologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/terapia , Antígeno CD56/metabolismo , Linhagem Celular Tumoral , Humanos , Ativação Linfocitária/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo
15.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202553

RESUMO

The cells of the immune system, particularly the T lymphocytes, have two main features that distinguish them from the cells of other tissues. They proliferate after activation and have the ability to move in tissues and organs. These characteristics compel them to develop metabolic plasticity in order to fulfil their immune function. This review focuses on the different known mechanisms that allow T cells to adapt their metabolism to the real-life circumstances they operate in, whether it is to exit quiescence, to differentiate into effector cells, or to participate in immune memory formation. Some of the metabolic adaptations to environmental variations that T cells are likely to undergo in their immune monitoring function are also discussed.


Assuntos
Metabolismo Energético , Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Diferenciação Celular/imunologia , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
16.
Front Immunol ; 12: 693269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220854

RESUMO

Chronic immune activation has been considered as the driving force for CD4+ T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+ and CD8+ subsets. In addition, it is accompanied by low CD4+ T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeans in vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , Ativação Linfocitária/imunologia , SARS-CoV-2/imunologia , ADP-Ribosil Ciclase 1/sangue , África , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , COVID-19/prevenção & controle , Antígenos HLA-DR/sangue , Humanos , Interleucina-10/sangue , Interleucina-4/sangue , Leucócitos Mononucleares/metabolismo , Glicoproteínas de Membrana/sangue , Receptores CCR5/sangue , Fator de Necrose Tumoral alfa/sangue
17.
Clin Pharmacol Ther ; 110(3): 607-615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34143437

RESUMO

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug-induced T-cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T-cell-mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA-associated drug reactions and the implications for future translation into clinical care.


Assuntos
Hipersensibilidade a Drogas/genética , Antígenos HLA/genética , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Alelos , Animais , Hipersensibilidade a Drogas/imunologia , Antígenos HLA/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Farmacogenética/métodos , Linfócitos T/imunologia
19.
Commun Biol ; 4(1): 681, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083746

RESUMO

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.


Assuntos
Chaperonina com TCP-1/imunologia , Proteostase/imunologia , Linfócitos T/imunologia , Timócitos/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismo , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteoma/imunologia , Proteoma/metabolismo , Proteostase/genética , Linfócitos T/citologia , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072296

RESUMO

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.


Assuntos
Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Suscetibilidade a Doenças , Genes Ligados ao Cromossomo X , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/metabolismo , Animais , Biomarcadores , Diacilglicerol Quinase/química , Ativação Enzimática , Estudos de Associação Genética/métodos , Loci Gênicos , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Transtornos Linfoproliferativos/diagnóstico , Ligação Proteica , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo
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