Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.024
Filtrar
1.
Mol Immunol ; 116: 167-173, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698163

RESUMO

Primary biliary cholangitis (PBC) is considered as a model of organ-specific autoimmune disease based on the serological findings of anti-mitochondrial antibodies (AMA), infiltrates of T cells, and selective destruction of epithelial cells in the liver. T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cholangitis (PBC). In this context, we used a combination of multiplex-PCR, Illumina sequencing and IMGT/HighV-QUEST for a standardized analysis of the T cell receptor ß-chain (TCRß) repertoire of CD4+naive T cells in PBC patients compared with healthy volunteers. Nonfunctional TCRs were used to study the pre-selection TCR repertoire, as they are not subject to functional selection (positive and negative selection). Functional TCRs were used to study the post-selection TCR repertoire. The results showed that there was not significant difference between PBC patients and healthy volunteers in TCRß diversity, CDR3 length distributions, degree of sequence sharing, and usage frequency of TRBV and TRBJ segments, no matter in Pre-selection or Post-selection repertoires. In conclusion, early events in thymic T cell development and repertoire generation are not abnormality in PBC patients. The breakdown of self-tolerance to autoantigen may be derived from other immunological dysregulation or environmental agents.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Cirrose Hepática Biliar/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto , Idoso , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Células Epiteliais/imunologia , Feminino , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Fígado/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex/métodos
2.
Mol Immunol ; 116: 174-179, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31704500

RESUMO

We considered the possibility that the greater the distance between an immune receptor V and J, the more likely the V usage. Such a hypothesis is supported by results from mouse experiments. And, such a hypothesis is consistent with the fundamental nature of recombination and genomic distance: the further the distance, the greater the chance of a DNA break. Thus, we exploited the vast dataset of V and J recombination reads available for the human TRA gene, particularly from cancer and blood specimens, to assess the frequency of TRAV usage with respect to distance from the TRAJ cluster. Results indicated that, indeed, over the entire TRAV cluster, there is a greater chance of V usage the further the distance from the J cluster. These results do not address causation, and are not consistent for certain individual V gene segments, but the results do indicate that overall, the larger the distance between the V and J gene segment cluster, the more likely the appearance of at least a subset of TRAV segments, particularly among tumor infiltrating lymphocytes. With a similar approach, the distal TRAV gene segments were also found to be more commonly associated with a subset of distal TRAJ segments. These results have implications for restrictions on the apparent TRA repertoire in disease settings.


Assuntos
Família Multigênica/genética , Neoplasias/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Humanos , Linfócitos do Interstício Tumoral/imunologia , Família Multigênica/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
3.
Nat Commun ; 10(1): 3569, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395875

RESUMO

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αßTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αßTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αßTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.


Assuntos
Carbamazepina/efeitos adversos , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Síndrome de Stevens-Johnson/imunologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Antígeno HLA-B15/genética , Antígeno HLA-B15/imunologia , Humanos , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/patologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/transplante
4.
Immunogenetics ; 71(8-9): 513-518, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31418051

RESUMO

Demonstration that immature CD4 + 8+ thymocytes contain T cell precursors that are subjected to positive and negative selection was the major step towards understanding how the adaptive immune system acquires the ability to distinguish foreign or abnormal (mutated or infected) self-cells from normal (healthy) cells. In the present review, the roles of TCR, CD4, CD8, and MHC molecules in intrathymic selection and some of the crucial experiments that contributed to the solution of the great immunological puzzle of self/nonself discrimination are described in an historical perspective. Recently, these experiments were highlighted by the immunological community by awarding the 2016 Novartis Prize for Immunology to Philippa Marrack, John Kappler, and Harald von Boehmer.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/imunologia , Sistema Imunitário/imunologia , Tolerância a Antígenos Próprios , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Timo/citologia
5.
Nat Immunol ; 20(9): 1244-1255, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31431722

RESUMO

Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified 5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated into CD44- naive T cells. MAIT cell positive selection required signaling through the adapter, SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes selected on either thymic epithelial cells or hematopoietic cells. The resulting model illustrates T cell lineage decisions.


Assuntos
Linhagem da Célula/imunologia , Células T Invariáveis Associadas à Mucosa/citologia , Células T Invariáveis Associadas à Mucosa/imunologia , Ribitol/análogos & derivados , Timócitos/citologia , Timócitos/imunologia , Uracila/análogos & derivados , Animais , Sequência de Bases , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores de Hialuronatos/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Ribitol/imunologia , Análise de Sequência de RNA , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Timo/citologia , Timo/imunologia , Uracila/imunologia
6.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373285

RESUMO

Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered a prototype of T-cell-mediated disease characterized by loss of tolerance to dietary gluten and the targeted killing of enterocytes by T-cell receptor αß intraepithelial lymphocytes. Accumulating evidence, however, indicates that the induction of a gluten-specific T helper-1 response must be preceded by the activation of the innate immune system. Mast cells are key players of the innate immune response and contribute to the pathogenesis of a multitude of diseases. Here, we review the results of studies aimed at investigating the role of mast cells in the pathogenesis of coeliac disease, showing that these cells increase in number during the progression of the disease and contribute to define a pro-inflammatory microenvironment.


Assuntos
Doença Celíaca/imunologia , Doença Celíaca/patologia , Gliadina/imunologia , Mastócitos/imunologia , Linfócitos T/imunologia , Doença Celíaca/genética , Enterócitos/metabolismo , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Mastócitos/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
7.
Scand J Immunol ; 90(5): e12806, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31276223

RESUMO

The Standard model of T cell recognition asserts that T cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus and that peripheral T cell repertoire has mild self-major histocompatibility complex (MHC) reactivity, known as MHC restriction of foreign antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope models suggest contradictory roles for complementarity-determining regions (CDRs) of the TCRs. Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR-MHC-conserved interaction. I suggest that double (CD4+ CD8+ )-positive (DP) developing thymocytes compete with their αßTCRs for binding to self-pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue-restricted antigens. The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal-centre B cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self-pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4+ Foxp3+ tTregs can be generated by mTECs via Aire-dependent and Aire-independent pathways, and additionally on thymic bone marrow-derived APCs including thymic Aire-expressing B cells. Thymic Tregs differ from the induced peripheral Tregs, which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes' competition for the highest binding to self-pMHC is the co-evolution of species-specific αßTCR V regions with MHC alleles.


Assuntos
Regiões Determinantes de Complementaridade/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Ativação Linfocitária/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Timo/imunologia , Fatores de Transcrição/metabolismo
8.
Braz J Infect Dis ; 23(3): 151-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31271732

RESUMO

BACKGROUND: HIV infection harms adaptive cellular immunity mechanisms. Long-term virological control by combined antiretroviral therapy (cART) reduces the risk of mycobacterial infections. Thus, we aimed to study cellular responses to mycobacterial antigens in 20 HIV-infected adolescents with at least one year of virological control (HIV-RNA <40 copies/mL) and 20 healthy adolescents. METHODS: We evaluated CD8 and γδ T-cell degranulation by measurement of CD107a membrane expression after stimulation with lysates from BCG (10 µg/mL) and H37RA Mycobacterium tuberculosis (Mtb, 10 µg/mL). Immune activation and antigen-presenting ability were also assessed by determination of HLA-DR, CD80, and CD86 markers. RESULTS: TCR γδ T-cell CD107a expression was similar between groups in response to mycobacterial antigens, and lower in the HIV-infected group in response to mitogen. Higher baseline HLA-DR expression and lower mycobacterial-stimulated expression was found within the HIV-infected group. CONCLUSIONS: Similar degranulation in stimulated CD8+ and TCR γδ T-cells from HIV-infected adolescents, when compared to healthy controls suggests long-term immunological preservation with immune reconstitution under successful cART. However, differences in HLA-DR expression may represent ongoing inflammation and lower specific responses in HIV-infected youth. These features may be relevant in the context of the precocity and severity of vertically acquired HIV infection.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Fármacos Anti-HIV/uso terapêutico , Antígenos de Bactérias/imunologia , Linfócitos T CD8-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tuberculose/imunologia , Apresentação do Antígeno/imunologia , Antígenos de Bactérias/efeitos dos fármacos , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Imunofenotipagem , Transmissão Vertical de Doença Infecciosa , Masculino , Estudos Prospectivos , Adulto Jovem
9.
Biochem Soc Trans ; 47(4): 1077-1089, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31249100

RESUMO

In T cell development, a pivotal decision-making stage, termed ß-selection, integrates a TCRß checkpoint to coordinate survival, proliferation and differentiation to an αß T cell. Here, we review how transcriptional regulation coordinates fate determination in early T cell development to enable ß-selection. Errors in this transcription control can trigger T cell acute lymphoblastic leukaemia. We describe how the ß-selection checkpoint goes awry in leukaemic transformation.


Assuntos
Carcinogênese , Sobrevivência Celular , Regulação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Linfócitos T/citologia , Transcrição Genética , Ativação Metabólica , Animais , Diferenciação Celular , Proliferação de Células , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia
10.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209405

RESUMO

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.


Assuntos
Autoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Desiminases de Arginina em Proteínas/metabolismo , Linfócitos T Reguladores/imunologia , Timo/citologia
11.
Immunology ; 157(4): 322-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31206171

RESUMO

Primary and chronic human immunodeficiency virus (HIV) infection alters γδ T-cell features. However, there is no evidence about early combined antiretroviral therapy (cART) and γδ T-cell dynamics. In the present study, HIV-positive individuals were divided into those with early primary infection (EPI) and those with late primary infection (LPI). The analysis of γδ T cells was performed by flow cytometry before and after therapy. Polyfunctional profile was assessed after in vitro peripheral blood mononuclear cell (PBMC) exposure to specific antigens. The results show that primary infection induced an expansion of Vδ1 T cells in LPI. Before treatment, a massive activation of γδ T-cell subsets was observed in both groups of patients, that correlated with disease progression and was significantly reduced after cART introduction. Despite this, CD107A-expressing Vδ1 T cells in both groups were significantly fewer than in healthy donors, but were restored by therapy introduction. Polyfunctional analysis of Vδ1 T cells from HIV-positive individuals revealed a lower frequency of CD107A+  CCL-4+ Vδ1 T-cell subsets than healthy donors that persists after therapy. Functional profile of Vδ2 was similar to that in healthy donors before therapy but, at 6 months, a lower frequency of CD107A, interferon-γ- or tumor necrosis factor-α-producing Vδ2 T cells was observed in the EPI group. Finally, individuals with LPI showed a lower frequency of quadruple-functional Vδ2 T-cell subset. In conclusion, during primary HIV infection, the baseline Vδ1 T-cell activation is correlated with immune reconstitution potential. Moreover, an altered γδ polyfunctional profile occurred, persisting after cART. Further studies are needed to understand whether a longer treatment of primary infection may increase γδ T-cell functionality.


Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Linfocitária/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Adulto , Quimiocina CCL4/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Interferon gama/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/imunologia
12.
PLoS One ; 14(5): e0216815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071196

RESUMO

Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αß T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αß T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an "NK cell-promoting" protocol to differentiate γδ T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic γδ T cells endowed with an array of NKRs and thus designated as "γδ natural killer T (γδ NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, γδ NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.


Assuntos
Antígenos de Neoplasias/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos Quiméricos/imunologia , Antígenos de Neoplasias/genética , Células HCT116 , Células Hep G2 , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células K562 , Células MCF-7 , Células T Matadoras Naturais/patologia , Neoplasias/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos Quiméricos/genética , Células THP-1
13.
Scand J Immunol ; 90(3): e12794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31141185

RESUMO

Natural killer T (NKT) cells are αß T cell receptor (TCR) expressing innate-like T cells that display natural killer (NK) cell markers. Based on TCR characteristics, they are divided into two groups restricted to the MHC class I-like molecule CD1d. Type I NKT cells, most extensively studied, are identified by a semi-invariant Vα14-Jα18 (mouse, Vα24-Jα18 in humans) TCR reactive to the prototypic ligand α-galactosylceramide presented on CD1d. In contrast, type II NKT cells display diverse TCR reacting to different CD1d-presented ligands. There are no reagents that identify all type II NKT cells, limiting their exploration. Here, we searched for novel type II NKT cells by comparing Jα18-/- MHCII-/- mice that harbour type II but not type I NKT cells, and CD1d-/- MHCII-/- mice, lacking all NKT cells. We identified significantly larger populations of CD4+ and CD4- CD8- (double negative, DN) TCRß+ cells expressing NKG2D or NKG2A/C/E in Jα18-/- MHCII-/- mice compared with CD1d-/- MHCII-/- mice, suggesting that 30%-50% of these cells were type II NKT cells. They expressed CD122, NK1.1, CXCR3 and intermediate/low levels of CD45RB. Further, the CD4+ subset was CD69+ , while the DN cells were CD49b+ and CD62L+ . Both subsets expressed the NKT cell-associated promyelocytic leukaemia zinc finger (PLZF) transcription factor and Tbet, while fewer cells expressed RORγt. NKG2D+ CD4+ and DN populations were producers of IFN-γ, but rarely IL-4 and IL-17. Taken together, we identify a novel subset of primary CD4+ and DN type II NKT cells that expresses NKG2 receptors have typical NKT cell phenotypes and a TH1-like cytokine production.


Assuntos
Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Biomarcadores/metabolismo , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Animais , Feminino , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células T Matadoras Naturais/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Nat Commun ; 10(1): 2243, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113973

RESUMO

Mucosal-associated invariant T (MAIT) cells express an invariant TRAV1/TRAJ33 TCR-α chain and are restricted to the MHC-I-like molecule, MR1. Whether MAIT cell development depends on this invariant TCR-α chain is unclear. Here we generate Traj33-deficient mice and show that they are highly depleted of MAIT cells; however, a residual population remains and can respond to exogenous antigen in vitro or pulmonary Legionella challenge in vivo. These residual cells include some that express Trav1+ TCRs with conservative Traj-gene substitutions, and others that express Trav1- TCRs with a broad range of Traj genes. We further report that human TRAV1-2- MR1-restricted T cells contain both MAIT-like and non-MAIT-like cells, as judged by their TCR repertoire, antigen reactivity and phenotypic features. These include a MAIT-like population that expresses a public, canonical TRAV36+ TRBV28+ TCR. Our findings highlight the TCR diversity and the resulting potential impact on antigen recognition by MR1-restricted T cells.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Legionelose/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Apresentação do Antígeno/imunologia , Modelos Animais de Doenças , Células HEK293 , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Legionella/imunologia , Legionelose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
15.
Scand J Immunol ; 90(2): e12790, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31127959

RESUMO

There is a sharp difference in how one views TCR structure-function-behaviour dependent on whether its recognition of major histocompatibility complex-encoded restriction elements (R) is germline selected or somatically generated. The generally accepted or Standard model is built on the assumption that recognition of R is by the V regions of the αß TCR, which is not driven by allele specificity, whereas the competing model posits that recognition of R is allele-specific. The establishing of allele-specific recognition of R by the TCR would rule out the Standard model and clear the road to a consideration of a competing construct, the Tritope model. Here, the case for allele-specific recognition (germline selected) is detailed making it obvious that the Standard model is untenable.


Assuntos
Alelos , Complexo Principal de Histocompatibilidade/imunologia , Modelos Biológicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Haplótipos/genética , Humanos , Polimorfismo Genético/genética
16.
PLoS Comput Biol ; 15(3): e1006874, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30830899

RESUMO

The T-cell (TCR) repertoire relies on the diversity of receptors composed of two chains, called α and ß, to recognize pathogens. Using results of high throughput sequencing and computational chain-pairing experiments of human TCR repertoires, we quantitively characterize the αß generation process. We estimate the probabilities of a rescue recombination of the ß chain on the second chromosome upon failure or success on the first chromosome. Unlike ß chains, α chains recombine simultaneously on both chromosomes, resulting in correlated statistics of the two genes which we predict using a mechanistic model. We find that ∼35% of cells express both α chains. Altogether, our statistical analysis gives a complete quantitative mechanistic picture that results in the observed correlations in the generative process. We learn that the probability to generate any TCRαß is lower than 10(-12) and estimate the generation diversity and sharing properties of the αß TCR repertoire.


Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Cromossomos Humanos , Humanos , Probabilidade , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Recombinação Genética
17.
PLoS One ; 14(3): e0213597, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30865691

RESUMO

Canine CD4+CD8α+ double-positive (dp) T cells of peripheral blood are a unique effector memory T cell subpopulation characterized by an increased expression of activation markers in comparison with conventional CD4+ or CD8α+ single-positive (sp) T cells. In this study, we investigated CD4+CD8α+ dp T cells in secondary lymphatic organs (i.e. mesenteric and tracheobronchial lymph nodes, spleen, Peyer's patches) and non-lymphatic tissues (i.e. lung and epithelium of the small intestine) within a homogeneous group of healthy Beagle dogs by multi-color flow cytometry. The aim of this systematic analysis was to identify the tissue-specific localization and characteristics of this distinct T cell subpopulation. Our results revealed a mature extrathymic CD1a-CD4+CD8α+ dp T cell population in all analyzed organs, with highest frequencies within Peyer's patches. Constitutive expression of the activation marker CD25 is a feature of many CD4+CD8α+ dp T cells independent of their localization and points to an effector phenotype. A proportion of lymph node CD4+CD8α+ dp T cells is FoxP3+ indicating regulatory potential. Within the intestinal environment, the cytotoxic marker granzyme B is expressed by CD4+CD8α+ dp intraepithelial lymphocytes. In addition, a fraction of CD4+CD8α+ dp intraepithelial lymphocytes and of mesenteric lymph node CD4+CD8α+ dp T cells is TCRγδ+. However, the main T cell receptor of all tissue-associated CD4+CD8α+ dp T cells could be identified as TCRαß. Interestingly, the majority of the CD4+CD8α+ dp T cell subpopulation expresses the unconventional CD8αα homodimer, in contrast to CD8α+ sp T cells, and CD4+CD8α+ dp thymocytes which are mainly CD8αß+. The presented data provide the basis for a functional analysis of tissue-specific CD4+CD8α+ dp T cells to elucidate their role in health and disease of dogs.


Assuntos
Antígenos CD4/imunologia , Antígenos CD8/imunologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Animais , Doenças do Cão/imunologia , Cães , Feminino , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Especificidade de Órgãos/imunologia
19.
Dev Comp Immunol ; 95: 96-100, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30768943

RESUMO

Milk provides mammalian neonates with nutritional support and passive immunity. This is particularly true in marsupials where young are born highly altricial and lacking many components of a fully functional adaptive immune system. Here we investigated the T cell populations in the mammaries of a lactating marsupial, the gray short-tailed opossum Monodelphis domestica. Immunohistochemistry confirmed the presence of T cells within the opossum mammaries throughout lactation. Results of quantifying transcript abundance for lymphocyte markers are consistent with γδ T cells being the most common T cell type within lactating mammaries. Numbers of γδ T cells appear to peak early during the first postnatal week, and then decline throughout lactation until weaning. In contrast, numbers of αß T cells and γµ T cells appear to be low to non-existent in the lactating mammaries. The results support an ancient and conserved role of immune cells in the evolution and function of mammalian mammary tissue.


Assuntos
Lactação/imunologia , Glândulas Mamárias Animais/imunologia , Monodelphis/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Monodelphis/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/metabolismo
20.
PLoS Pathog ; 15(2): e1007567, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789961

RESUMO

Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αß and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered "unconventional," in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, "Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens," sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.


Assuntos
Vigilância Imunológica/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Animais , Antígenos , Antígenos HLA , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA