RESUMO
In the adult mammalian brain, newborn granule cells are continuously integrated into hippocampal circuits, and the fine-tuning of this process is important for hippocampal function. Thus, the identification of factors that control adult neural stem cells (NSCs) maintenance, differentiation and integration is essential. Here we show that the deletion of the iron trafficking protein lipocalin-2 (LCN2) induces deficits in NSCs proliferation and commitment, with impact on the hippocampal-dependent contextual fear discriminative task. Mice deficient in LCN2 present an increase in the NSCs population, as a consequence of a G0/G1 cell cycle arrest induced by increased endogenous oxidative stress. Of notice, supplementation with the iron-chelating agent deferoxamine rescues NSCs oxidative stress, promotes cell cycle progression and improves contextual fear conditioning. LCN2 is, therefore, a novel key modulator of neurogenesis that, through iron, controls NSCs cell cycle progression and death, self-renewal, proliferation and differentiation and, ultimately, hippocampal function.
Assuntos
Discriminação Psicológica/fisiologia , Lipocalina-2/metabolismo , Neurogênese/fisiologia , Animais , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Giro Denteado/metabolismo , Medo/fisiologia , Hipocampo/citologia , Hipocampo/metabolismo , Lipocalina-2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismoRESUMO
BACKGROUND: Commercial availability of serological tests to evaluate immunoglobulins (Ig) targeting severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has grown exponentially since the start of the coronavirus disease 2019 (COVID-19) outbreak. Thorough validation of these tests is important before use as epidemiological tools to infer seroprevalence in specific populations and as diagnostic tools to complement molecular approaches (e.g., quantitative reverse transcription-polymerase chain reaction). METHODS: Commercial serological tests from 11 suppliers were assayed side-by-side using 126 samples from SARS-CoV-2-infected inpatients and 36 from healthy and HIV-infected individuals. RESULTS: The majority of the tests assayed have >95% specificity. For the sensitivity calculation, samples were stratified by days since symptoms onset; sensitivity peaks at 16-21 days for IgM and IgA (maximum 91.2%, Euroimmun) and, dependant on the test, at 16-21 or >21 days for IgG (maximum 94.1%, Snibe). Data from semiquantitative tests show that patients with a severe clinical presentation have lower levels of Ig targeting SARS-CoV-2 at <10 days since symptoms onset and higher levels at >21 days, compared to patients with a non-severe presentation. CONCLUSIONS: This study highlights the heterogeneity of sensitivity and generally high specificity of the serological tests and establishes a basis for their usefulness to complement diagnostic techniques and population seroprevalence studies.
Assuntos
Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Estudos SoroepidemiológicosRESUMO
A system to innocuously visualize T cell lineage commitment is described. Using a "knock-in" approach, we have generated mice expressing a beta-galactosidase reporter in place of CD4; expression of beta-galactosidase in these animals appears to be an accurate and early indicator of CD4 gene transcription. We have exploited this knock-in line to trace CD4/CD8 lineage commitment in the thymus, avoiding important pitfalls of past experimental approaches. Our results argue in favor of a selective model of thymocyte commitment, demonstrating a fundamentally symmetrical process: engagement of either class of major histocompatibility complex (MHC) molecule by a differentiating CD4(+)CD8(+) cell can give rise to T cell antigen receptor (TCR)hi thymocytes of either lineage. Key findings include (a) direct demonstration of a substantial number of CD4-committed, receptor/coreceptor-mismatched cells in MHC class II- deficient mice, a critical prediction of the selective model; (b) highly efficient rescue of such "mismatched" intermediates by forced expression of CD8 in a TCR transgenic line, and an explanation of why previous experiments of this nature were less successful-a major past criticism of the selective model; (c) direct demonstration of an analogous, though smaller, population of CD8-committed mismatched intermediates in class I-deficient animals. Finally, we found no evidence of a CD4 default pathway.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Timo/citologia , Animais , Antígenos CD/análise , Antígenos CD/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Cultivadas , Regulação para Baixo , Genes Reporter , Heterozigoto , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , RNA Mensageiro/análise , Recombinação Genética , Microglobulina beta-2/genética , Microglobulina beta-2/metabolismo , beta-Galactosidase/análise , beta-Galactosidase/genéticaRESUMO
Research on infectious diseases using animal models has been a successful example of translational research. However, because chronic infections are still one of the main causes of death and disability in the world, it is expected that a great number of mice will continue to be used to address this subject. Although increasing awareness regarding animal welfare has led to novel recommendations for animal housing enrichment, studies evaluating the impact of these modifications on the immune response to infection are lacking. The present study shows that validated and recommended simple environmental enrichment does not interfere with the immune response to chronic infection with Mycobacterium avium for up to 20 weeks, as assessed by the bacterial load in the spleen and lung, by the number and activation status of the main cell populations of the immune system and the serum concentration of interferon-gamma. Therefore, enrichment can be encouraged without concern regarding comparability of results among laboratories studying this type of chronic infections.
Assuntos
Abrigo para Animais , Mycobacterium avium/imunologia , Tuberculose/imunologia , Tuberculose/veterinária , Animais , Separação Celular , Doença Crônica , Feminino , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Numerous species of mammals are susceptible to Mycobacterium bovis, the causative agent of bovine tuberculosis (TB). Several wildlife hosts have emerged as reservoirs of M. bovis infection for domestic livestock in different countries. In the present study, blood samples were collected from Eurasian badgers (n=1532), white-tailed deer (n=463), brushtail possums (n=129), and wild boar (n=177) for evaluation of antibody responses to M. bovis infection by a lateral-flow rapid test (RT) and multiantigen print immunoassay (MAPIA). Magnitude of the antibody responses and antigen recognition patterns varied among the animals as determined by MAPIA; however, MPB83 was the most commonly recognized antigen for each host studied. Other seroreactive antigens included ESAT-6, CFP10, and MPB70. The agreement of the RT with culture results varied from 74% for possums to 81% for badgers to 90% for wild boar to 97% for white-tailed deer. Small numbers of wild boar and deer exposed to M. avium infection or paratuberculosis, respectively, did not cross-react in the RT, supporting the high specificity of the assay. In deer, whole blood samples reacted similarly to corresponding serum specimens (97% concordance), demonstrating the potential for field application. As previously demonstrated for badgers and deer, antibody responses to M. bovis infection in wild boar were positively associated with advanced disease. Together, these findings suggest that a rapid TB assay such as the RT may provide a useful screening tool for certain wildlife species that may be implicated in the maintenance and transmission of M. bovis infection to domestic livestock.
Assuntos
Animais Selvagens/microbiologia , Mycobacterium bovis/isolamento & purificação , Testes Sorológicos/veterinária , Tuberculose Bovina/epidemiologia , Animais , Animais Selvagens/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Bovinos , Cervos/sangue , Cervos/microbiologia , Mustelidae/sangue , Mustelidae/microbiologia , Nova Zelândia/epidemiologia , Portugal/epidemiologia , Espanha/epidemiologia , Sus scrofa/sangue , Sus scrofa/microbiologia , Trichosurus/sangue , Trichosurus/microbiologia , Tuberculose Bovina/sangue , Reino Unido/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Increased interest is being raised on the interaction between systemic inflammation and the brain. The choroid plexus (CP) constitutes a monolayer of epithelial cells located within the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF). Despite the knowledge that the CP capillaries are fenestrated, allowing free passage of molecules and cells, the involvement of the vast blood-brain boundary represented by the CP/CSF barrier in brain inflammatory processes has seldom been considered. In the present study we investigate, in mice, how the expression of genes encoding major constitutively expressed CP proteins is influenced by a systemic inflammatory stimulus. Confirming that the CP responds to peripheral inflammation, the messenger RNA (mRNA) levels of the pro-inflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha are rapidly induced. As for the constitutively expressed proteins, while the mRNA for genes encoding transthyretin and transferrin remain unaltered by the inflammatory challenge, that for prostaglandin D2 synthase (LPTGDS) is up-regulated at 6 h, and stays up-regulated up to 24 h after lipopolysacharide administration. Accordingly, LPTGDS CSF levels are also augmented. LPTGDS catalyzes the synthesis of the major prostanoid of the CNS and, being increased in the CSF, might mediate immune signaling into the brain. These observations emphasize that the CP must be considered a relevant mediator of immune signals between the periphery and the brain.
Assuntos
Plexo Corióideo/metabolismo , Plexo Corióideo/patologia , Expressão Gênica/fisiologia , Inflamação Neurogênica/patologia , Animais , Plexo Corióideo/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inflamação Neurogênica/induzido quimicamente , Prostaglandinas D/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This paper presents a novel poly(dimethylsiloxane) (PDMS) microfluidic immunosensor that integrates a complementary metal-oxide-semiconductor (CMOS) optical detection system for a rapid and highly-sensitive quantification of salivary cortisol. The simple and non-invasive method of saliva sampling provides an interesting alternative to the blood, allowing a fast sampling at short intervals, relevant for many clinical diagnostic applications. The developed approach is based on the covalent immobilization of a coating antibody (Ab), a polyclonal anti-IgG, onto a treated PDMS surface. The coating Ab binds the capture Ab, an IgG specific for cortisol, allowing its correct orientation. Horseradish peroxidase (HRP)-labelled cortisol is added to compete with the cortisol in the sample, for the capture Ab binding sites. The HRP-labelled cortisol, bonded to the capture Ab, is measured through the HRP enzyme and the tetramethylbenzidine (TMB) substrate reaction. The cortisol quantification is performed by colorimetric detection of HRP-labelled cortisol, through optical absorption at 450nm, using a CMOS silicon photodiode as the photodetector. Under the developed optimized conditions presented here, e.g., microfluidic channels geometry, immobilization method and immunoassay conditions, the immunosensor shows a linear range of detection between 0.01-20ng/mL, a limit of detection (LOD) of 18pg/mL and an analysis time of 35min, featuring a great potential for point-of-care applications requiring continuous monitoring of the salivary cortisol levels during a circadian cycle.
Assuntos
Técnicas Biossensoriais/métodos , Hidrocortisona/isolamento & purificação , Nanopartículas Metálicas/química , Saliva/química , Anticorpos Anti-Idiotípicos/química , Anticorpos Anti-Idiotípicos/imunologia , Ouro/química , Peroxidase do Rábano Silvestre/química , Humanos , Hidrocortisona/química , Imunoensaio/métodos , Microfluídica/instrumentaçãoRESUMO
Interferon gamma (IFNγ) is a pro-inflammatory cytokine, first described as a secreted molecule capable of interfering with viral replication. Since then, numerous other important actions in the context of the immune response to invading pathogens (including those invading the brain) have been ascribed to this pleiotropic cytokine. Nevertheless, the precise role of IFNγ in neuropsychiatric and neurodegenerative disorders, and its possible contribution to the regulation of normal brain function, remains enigmatic. This review integrates and considers current knowledge about IFNγ actions with accumulating evidence of its importance on neurocytogenesis, synaptic plasticity and neurodegeneration within the framework of brain health and disease.
Assuntos
Sistema Nervoso Central/metabolismo , Interferon gama/metabolismo , Doenças Neurodegenerativas/patologia , Plasticidade Neuronal/fisiologia , Animais , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , HumanosRESUMO
BACKGROUND: Tuberculosis (TB) is a major concern among high-risk populations such as the homeless. OBJECTIVES: To evaluate TB incidence and treatment outcomes among homeless patients in Portugal and to identify predictors of unsuccessful TB treatment outcomes among the homeless. DESIGN: This was a retrospective cohort study of all TB patients notified in Portugal from 2008 to 2014. Characteristics of homeless TB patients were assessed and predictors of unsuccessful TB treatment were determined using logistic regression. RESULTS: TB incidence among the homeless was 122/100,000 homeless persons and was positively correlated with TB incidence among non-homeless persons. Homeless TB patients had a higher prevalence of alcohol and/or drug use, human immunodeficiency virus (HIV) co-infection, cavitary TB and smear positivity. The rate of unsuccessful treatment outcomes among the homeless was 28.6%, and was significantly associated with increased age, injection drug use (IDU) and HIV co-infection. CONCLUSION: TB incidence among homeless persons was five times that among the non-homeless, and higher in regions with greater TB incidence among non-homeless persons. The successful treatment outcome rate was lower. Predictors of unsuccessful treatment were age, IDU and HIV co-infection. Integrated TB programmes targeting homeless and non-homeless patients, with measures targeting specific characteristics, may contribute to TB elimination in Portugal.
Assuntos
Antituberculosos/administração & dosagem , Infecções por HIV/epidemiologia , Pessoas Mal Alojadas/estatística & dados numéricos , Tuberculose/epidemiologia , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Coortes , Coinfecção , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Resultado do Tratamento , Tuberculose/tratamento farmacológicoRESUMO
Cognitive functioning can be differentially modulated by components of the immune system. Interferon-γ (IFNγ) is a pro-inflammatory cytokine whose production is altered in many conditions displaying some degree of cognitive deficits, although its role in cognitive functioning is still unclear. Here we show that the absence of IFNγ selectively enhances cognitive behaviours in tasks in which the hippocampus is implicated. Moreover, the absence of IFNγ leads to volumetric and cell density changes that are restricted to the dorsal part of the hippocampus. In the dorsal hippocampus, the absence of this pro-inflammatory cytokine leads to an increase in the numbers of newly born neurons in the subgranular zone of the dentate gyrus (DG), an adult neurogenic niche known to support learning and memory, and to an enlargement of the dendritic arborization of DG granule and cornu ammonis (CA)1 pyramidal neurons. Moreover, it also modestly impacts synaptic plasticity, by decreasing the paired-pulse facilitation in the Schaffer collateral to CA1 pyramidal cell synapses. Taken together, our results provide evidence that IFNγ is a negative regulator of hippocampal functioning, as its absence positively impacts on dorsal hippocampus structure, cell density, neuronal morphology and synaptic plasticity. Importantly, these neuroplastic changes are associated with improved performance in learning and memory tasks. Therefore, blockage of the IFNγ signalling may present as promising therapeutic targets for the treatment of inflammation-associated cognitive dysfunction.
Assuntos
Cognição/fisiologia , Hipocampo/fisiologia , Interferon gama , Plasticidade Neuronal/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The production, accumulation and aggregation of amyloid beta (Aß) peptides in Alzheimer's disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Aß aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Aß1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Aß1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Aß toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.
Assuntos
Proteínas de Fase Aguda/genética , Peptídeos beta-Amiloides/farmacologia , Proteínas Reguladoras de Apoptose/biossíntese , Astrócitos/metabolismo , Lipocalinas/biossíntese , Lipocalinas/genética , Proteínas de Membrana/biossíntese , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas/biossíntese , Doença de Alzheimer , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/citologia , Proteína 11 Semelhante a Bcl-2 , Células Cultivadas , Células Epiteliais/metabolismo , Heme Oxigenase (Desciclizante)/biossíntese , Inflamação/imunologia , Ferro/metabolismo , Lipocalina-2 , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/metabolismo , RatosRESUMO
The aim of this study was to compare two diagnostic methods for the detection of Mycobacterium avium complex (MAC) infection in lymph nodes with granulomatous lymphadenitis from slaughtered domestic pigs. Fifty affected lymph nodes were collected from 50 pigs and examined microscopically and by polymerase chain reaction (PCR). Microscopically, granulomatous lesions were observed in 92% of the samples, consisting mostly of central necrosis (78%) with dystrophic calcification (46%) and associated with inflammatory infiltration by epithelioid giant cells, lymphocytes, neutrophils (92%), eosinophils (60%) and Langhans-type cells (70%). In 64% of the lesions, a capsule of connective tissue was found. Acid-fast bacilli were observed in all cases. PCR detected DNA from Mycobacterium spp. in 82% (41/50) of the lymph nodes. MAC was confirmed in 58% (24/41) and M. avium avium/silvaticum subspecies in 39% (16/41). The results of this study suggest that combined histopathology and PCR of lymph nodes are useful in the diagnosis of granulomatous lymphadenitis in slaughtered pigs.
Assuntos
Granuloma/veterinária , Mycobacterium avium/isolamento & purificação , Doenças dos Suínos/diagnóstico , Tuberculose dos Linfonodos/veterinária , Tuberculose/veterinária , Animais , Calcinose/microbiologia , Calcinose/patologia , Calcinose/veterinária , Contagem de Células/veterinária , DNA Bacteriano/análise , Eosinófilos/patologia , Células Epitelioides/patologia , Células Gigantes/patologia , Granuloma/diagnóstico , Granuloma/microbiologia , Células de Langerhans/patologia , Linfonodos/microbiologia , Linfócitos/patologia , Necrose/microbiologia , Necrose/patologia , Necrose/veterinária , Neutrófilos/patologia , Reação em Cadeia da Polimerase/veterinária , Sus scrofa , Suínos , Doenças dos Suínos/microbiologia , Tuberculose/diagnóstico , Tuberculose/microbiologia , Tuberculose dos Linfonodos/diagnóstico , Tuberculose dos Linfonodos/microbiologiaRESUMO
Iron is essential for normal cellular homeostasis but in excess promotes free radical formation and is detrimental. Therefore, iron metabolism is tightly regulated. Here, we show that mechanisms regulating systemic iron metabolism may also control iron release into the brain at the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. Intraperitoneal administration of lipopolysaccharide (LPS) in mice triggers a transient transcription of the gene encoding for hepcidin, a key regulator of iron homeostasis, in the choroid plexus, which correlated with increased detection of pro-hepcidin in the CSF. Similarly, the expression of several other iron-related genes is influenced in the choroid plexus by the inflammatory stimulus. Using primary cultures of rat choroid plexus epithelial cells, we show that this response is triggered not only directly by LPS but also by molecules whose expression increases in the blood in response to inflammation, such as IL-6. Intracellular conveyors of these signaling molecules include signal transducer and activator of transcription 3, which becomes phosphorylated, and SMAD family member 4, whose mRNA levels increase soon after LPS administration. This novel role for the choroid plexus-CSF barrier in regulating iron metabolism may be particularly relevant to restrict iron availability for microorganism growth, and in neurodegenerative diseases in which an inflammatory underlying component has been reported.
Assuntos
Plexo Corióideo/metabolismo , Homeostase/fisiologia , Inflamação/metabolismo , Ferro/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Células Cultivadas , Plexo Corióideo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Hepcidinas , Inflamação/induzido quimicamente , Inflamação/patologia , Injeções Intraperitoneais , Interleucina-6/sangue , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Proteína Smad4/metabolismoRESUMO
By combining a TCRbeta transgene with a TCRalpha minilocus comprised of a single V and two J gene segments, we engineered a mouse line exhibiting ample but focused TCR diversity, restricted to CDR3alpha. Using single-cell PCR and high-throughput sequencing, we have exploited this system to scrutinize T cell repertoire selection and evolution. Some striking observations emerged: (1) thymic selection produces a repertoire that is very "bumpy," with marked overrepresentation of a subset of sequences; (2) MHC class I- and class II-restricted TCRs can be distinguished by minute, single-residue changes in CDR3alpha; and (3) homeostatic expansion and survival in the periphery can markedly remold the postselection repertoire, likely reflecting variability in the potential of cells displaying different TCRs to respond to homeostatic cues.
Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Timo/citologia , Timo/imunologiaRESUMO
As a new slant on T lymphocyte repertoire selection, we have examined batteries of TCR sequences in thymi from transgenic mice engineered to exhibit limited, focussed TCR diversity. We have tracked the fate of differentiating thymocytes expressing a set of particular TCR through the positive selection process. Subtly different TCR sequences can promote different maturation pathways and commitment choices. Two distinct routes are followed by CD8-lineage cells interacting with MHC class I molecules, via TCR(hi) CD4(+)CD8(+) or CD4(+)CD8(int) intermediates, while CD4-lineage cells mature exclusively via a CD4(+)CD8(int) stage. The CD8-lineage routes are partially exclusive, indicating that the latter cell type is not always preceded by the former. The distribution of sequences also indicates that CD4 / CD8-lineage commitment is not strictly correlated with the class of MHC molecule engaged, and that some mechanism prevents mismatched intermediates from achieving full maturity.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Timo/imunologia , Sequência de Aminoácidos , Animais , Linhagem da Célula , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Imunológicos , Células-Tronco/imunologiaRESUMO
The outcome of positive selection of T lymphocytes is that there is a close match between the lineage adopted by a particular cell (CD4+ or CD8+) and the specificity of the T-cell receptor for the class of Major Histocompatibility Complex molecule recognized. How this match is obtained has been a matter of debate. We review the evidence, from recent and older experiments, that indicates that the process follows a selective logic, rather than an instructive one.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Animais , Diferenciação Celular , Linhagem da Célula , HumanosRESUMO
Some TCR variable regions are preferentially expressed in CD4+ or CD8+ T cells, reflecting a predilection for interacting with MHC class II or class I molecules. The molecular basis for MHC class bias has been studied previously, in particular for V alpha 3 family members, pointing to a dominant role for two amino acid positions in complementary-determining regions (CDRs) 1 and 2. We have evaluated the generality of these findings by examining the MHC class bias of V alpha 2 family members, an attractive system because it shows more variability within the CDR1 and -2, exhibits variation in the framework regions, and includes a member for which the crystal structure has been determined. We find that preferential recognition of MHC class I or II molecules does not always depend on residues at the same positions of CDR1 and -2; rules for one family may be reversed in another. Instead, there are multiple influences exerted by various CDR1/2 positions as well as the CDR3s of both the TCR alpha- and TCR beta-chains.