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2.
Semin Cell Dev Biol ; 85: 132-142, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29438807

RESUMO

We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Linfócitos/metabolismo , Animais , Humanos , Linfócitos/citologia
3.
Semin Cell Dev Biol ; 85: 86-97, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29292221

RESUMO

The complement system is a complex and autoregulated multistep cascade at the interface of innate and adaptive immunity. It is activated by immune complexes or apoptotic cells (classical pathway), pathogen-associated glycoproteins (lectin pathway) or a variety of molecular and cellular surfaces (alternative pathway). Upon activation, complement triggers the generation of proteolytic fragments that allow the elimination of the activating surface by enhancing inflammation, opsonization, phagocytosis, and cellular lysis. Moreover, complement efficiently discriminates self from non-self surfaces by means of soluble and membrane-bound complement regulators which are critical for innate self-tolerance. Complement deficiency or dysfunction disturb complement homeostasis and give rise to diseases as diverse as bacterial infections, autoimmunity, or renal and neurological disorders. Research on complement-targeted therapies is an expanding field that has already improved the prognosis of severe diseases such as atypical Haemolytic Uremic syndrome or Paroxysmal Nocturnal Haemoglobinuria. Therefore, complement analysis and monitoring provides valuable information with deep implications for diagnosis and therapy. In addition to its important role as an extracellular defense system, it has now become evident that complement is also present intracellularly, and its activation has profound implications for leukocyte survival and function. In this review, we summarize the essential, up-to-date information on the use of complement as a diagnostic and therapeutic tool in the clinics.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/imunologia , Proteínas do Sistema Complemento/imunologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/imunologia , Sepse/diagnóstico , Sepse/imunologia , Doenças Autoimunes/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Tolerância Imunológica , Imunidade Inata
4.
Blood ; 131(21): 2335-2344, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29653965

RESUMO

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.


Assuntos
Complexo CD3/genética , Imunomodulação , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Biomarcadores , Complexo CD3/metabolismo , Expressão Gênica , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo
6.
Blood ; 130(10): 1205-1208, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28743717

RESUMO

Mutations in T-cell antigen receptor (TCR) subunit genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia. Here, detailed analyses of spontaneously arising somatic mutations that recover CD247, and thus TCR expression, in a newly identified CD247-deficient patient are described. The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression, but not as efficiently as wild-type CD247. Multiple mutations were found in CD247 complementary DNAs (cDNAs) cloned from the patient as well as in cDNA and genomic DNA from other individuals, suggesting that genetic variation in this gene is frequent. Analyses of other genes mutated in primary immunodeficiency diseases (PIDs) where reversions have been described also revealed a higher rate of mutation than that observed for genes mutated in PIDs where revertants have not been identified or control genes. These data support the hypothesis that the occurrence of somatic mutations that may reconstitute genetic defects in PID is related to an increased propensity of those genes to mutate.


Assuntos
Complexo CD3/genética , Reparo do DNA/genética , Regulação da Expressão Gênica , Síndromes de Imunodeficiência/genética , Humanos , Leucócitos Mononucleares/metabolismo , Mutação/genética , Probabilidade
7.
J Biol Chem ; 292(23): 9680-9689, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28446606

RESUMO

A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.


Assuntos
Aminopeptidases/imunologia , Síndrome de Behçet/imunologia , Antígeno HLA-B51/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Peptídeos/imunologia , Polimorfismo Genético/imunologia , Aminopeptidases/genética , Síndrome de Behçet/genética , Linhagem Celular , Antígeno HLA-B51/genética , Humanos , Células Matadoras Naturais/imunologia , Antígenos de Histocompatibilidade Menor/genética , Peptídeos/genética , Domínios Proteicos , Linfócitos T/imunologia
8.
Front Microbiol ; 8: 541, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28443070

RESUMO

The Gram-positive anaerobic human pathogenic bacterium Atopobium vaginae causes most diagnosed cases of bacterial vaginosis as well as opportunistic infections in immunocompromised patients. In addition to its well-established role in carbohydrate metabolism, D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Streptococcus pyogenes and S. pneumoniae have been reported to act as extracellular virulence factors during streptococcal infections. Here, we report the crystal structure of GAPDH from A. vaginae (AvGAPDH) at 2.19 Å resolution. The refined model has a crystallographic Rfree of 22.6%. AvGAPDH is a homotetramer wherein each subunit is bound to a nicotinamide adenine dinucleotide (NAD+) molecule. The AvGAPDH enzyme fulfills essential glycolytic as well as moonlight (non-glycolytic) functions, both of which might be targets of chemotherapeutic intervention. We report that AvGAPDH interacts in vitro with the human C5a anaphylatoxin and inhibits C5a-specific granulocyte chemotaxis, thereby suggesting the participation of AvGAPDH in complement-targeted immunoevasion in a context of infection. The availability of high-quality structures of AvGAPDH and other homologous virulence factors from Gram-positive pathogens is critical for drug discovery programs. In this study, sequence and structural differences between AvGAPDH and related bacterial and eukaryotic GAPDH enzymes are reported in an effort to understand how to subvert the immunoevasive properties of GAPDH and evaluate the potential of AvGAPDH as a druggable target.

10.
Mol Immunol ; 84: 10-16, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27919436

RESUMO

The complement system is reemerging in the last few years not only as key element of innate immunity against pathogens, but also as a main regulator of local adaptive responses, affecting dendritic cells as well as T and B lymphocytes. We review data showing that leucocytes are capable of significant autocrine synthesis of complement proteins, and express a large range of complement receptors, which in turn regulate their differentiation and effector functions while cross talking with other innate receptors such as Toll-like receptors. Other unconventional roles of complement proteins are reviewed, including their impact in non-leukocytes and their intracellular cleavage by vesicular proteases, which generate critical cues required for T cell function. Thus, leucocytes are very much aware of complement-derived information, both extracellular and intracellular, to elaborate their responses, offering rich avenues for therapeutic intervention and new hypothesis for conserved major histocompatibility complex complotypes.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Animais , Humanos
11.
Nat Immunol ; 17(6): 721-727, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27043412

RESUMO

The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g(+/-) Cd3d(+/-) (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on γδ T cells. CD3DH mice had normal numbers and phenotypes of αß thymocyte subsets, but impaired differentiation of fetal Vγ6(+) (but not Vγ4(+)) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122(+) NK1.1(+) γδ T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-γ(+) γδ T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory γδ T cell subsets and their impact on pathophysiology.


Assuntos
Diferenciação Celular , Inflamação/imunologia , Malária Cerebral/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/fisiologia , Linfócitos T/fisiologia , Timo/imunologia , Animais , Antígenos Ly/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de Sinais
16.
J Clin Invest ; 124(12): 5239-48, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25365219

RESUMO

Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Regulação da Expressão Gênica , Doenças Genéticas Inatas , Hematopoese , Síndromes de Imunodeficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B , Linfócitos B/imunologia , Linfócitos B/patologia , Pré-Escolar , Modelos Animais de Doenças , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Hematopoese/genética , Hematopoese/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Camundongos , Células Mieloides/imunologia , Células Mieloides/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
17.
Cell Rep ; 7(5): 1704-1715, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24857663

RESUMO

Activation of the T cell receptor (TCR) by antigen is the key step in adaptive immunity. In the αßTCR, antigen induces a conformational change at the CD3 subunits (CD3 CC) that is absolutely required for αßTCR activation. Here, we demonstrate that the CD3 CC is not induced by antigen stimulation of the mouse G8 or the human Vγ9Vδ2 γδTCR. We find that there is a fundamental difference between the activation mechanisms of the αßTCR and γδTCR that map to the constant regions of the TCRαß/γδ heterodimers. Enforced induction of CD3 CC with a less commonly used monoclonal anti-CD3 promoted proximal γδTCR signaling but inhibited cytokine secretion. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human γδ T cells. Thus, manipulation of the CD3 CC might be exploited to improve clinical γδ T cell-based immunotherapies.


Assuntos
Complexo CD3/química , Citotoxicidade Imunológica , Receptores de Antígenos de Linfócitos T gama-delta/química , Animais , Complexo CD3/imunologia , Linhagem Celular , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Conformação Proteica , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia
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