RESUMEN
T follicular helper (Tfh) and regulatory (Tfr) cells are terminally differentiated cells found in germinal centers (GCs), specialized secondary lymphoid organ structures dedicated to antibody production. As such, follicular T (Tfol) cells are supposed to be specific for immunizing antigens, which has been reported for Tfh cells but is debated for Tfr cells. Here, we used high-throughput T cell receptor (TCR) sequencing to analyze the repertoires of Tfh and Tfr cells, at homeostasis and after immunization with self- or foreign antigens. We observed that, whatever the conditions, Tfh and Tfr cell repertoires are less diverse than those of effector T cells and Treg cells of the same tissues; surprisingly, these repertoires still represent thousands of different sequences, even after immunization with a single antigen that induces a 10-fold increase in Tfol cell numbers. Thorough analysis of the sharing and network of TCR sequences revealed that a specific response to the immunizing antigen can only, but hardly, be detected in Tfh cells immunized with a foreign antigen and Tfr cells immunized with a self-antigen. These antigen-specific responses are obscured by a global stimulation of Tfh and Tfr cells that appears to be antigen-independent. Altogether, our results suggest a major bystander Tfol cell activation during the immune response in the GCs.
Asunto(s)
Centro Germinal/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Formación de Anticuerpos/inmunología , Antígenos/inmunología , Linfocitos B/inmunología , Femenino , Perfilación de la Expresión Génica/métodos , Centro Germinal/citología , Centro Germinal/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Ratones Endogámicos NOD , Modelos Animales , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Análisis de Secuencia de ADN , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
AIMS: Premature coronary artery disease (CAD) is an aggressive disease with multiple recurrences mostly related to new coronary lesions. This study aimed to compare coronary plaque characteristics of individuals with premature CAD with those of incidental plaques found in matched individuals free of overt cardiovascular disease, using coronary computed tomography angiography (CCTA). METHODS AND RESULTS: Of 1552 consecutive individuals who underwent CCTA, 106 individuals with history of acute or stable obstructive CAD ≤45 years were matched by age, sex, smoking status, cardiovascular heredity, and dyslipidaemia with 106 controls. CCTA were analysed for Coronary Artery Disease Reporting and Data System score, plaque composition, and high-risk plaque (HRP) features, including spotty calcification, positive remodelling, low attenuation, and napkin-ring sign. The characteristics of 348 premature CAD plaques were compared with those of 167 incidental coronary plaques of matched controls. The prevalence of non-calcified plaques was higher among individuals with premature CAD (65.1 vs. 30.2%, P < 0.001), as well as spotty calcification (42.5 vs. 17.9%, P < 0.001), positive remodelling (41.5 vs. 9.4%, P < 0.001), low attenuation (24.5 vs. 3.8%, P < 0.001), and napkin-ring sign (1.9 vs. 0.0%). They exhibited an average of 2.2 (2.7) HRP, while the control group displayed 0.4 (0.8) HRP (P < 0.001). Within a median follow-up of 24 (16, 34) months, individuals with premature CAD and ischaemic recurrence (n = 24) had more HRP [4.3 (3.9)] than those without ischaemic recurrence [1.5 (1.9)], mostly non-calcified with low attenuation and positive remodelling. CONCLUSION: Coronary atherosclerosis in individuals with premature CAD is characterized by a high and predominant burden of non-calcified plaque and unusual high prevalence of HRP, contributing to disease progression with multiple recurrences. A comprehensive qualitative CCTA assessment of plaque characteristics may further risk stratify our patients, beyond cardiovascular risk factors.
Asunto(s)
Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/patología , Angiografía Coronaria/métodos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Tomografía Computarizada por Rayos X , Corazón , Angiografía por Tomografía Computarizada/métodos , Factores de Riesgo , Vasos Coronarios/patología , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: The PRECISE criteria for serial multiparametric magnetic resonance imaging (MRI) of the prostate during active surveillance recommend the use of a dedicated scoring system (PRECISE score) to assess the likelihood of clinically significant radiological change. This pilot study assesses the effect of an interactive teaching course on prostate MRI during active surveillance in assessing radiological change in serial imaging. METHODS: Eleven radiology fellows and registrars with different experience in prostate MRI reading participated in a dedicated teaching course where they initially evaluated radiological change (based on their previous training in prostate MRI reading) independently in fifteen patients on active surveillance (baseline and follow-up scan), and then attended a lecture on the PRECISE score. The initial scans were reviewed for teaching purposes and afterwards the participants re-assessed the degree of radiological change in a new set of images (from fifteen different patients) applying the PRECISE score. Receiver operating characteristic analysis was performed. Confirmatory biopsies and PRECISE scores given in consensus by two radiologists (involved in the original draft of the PRECISE score) were the reference standard. RESULTS: There was a significant improvement in the average area under the curve (AUC) for the assessment of radiological change from baseline (AUC: 0.60 [Confidence Intervals: 0.51-0.69] to post-teaching (AUC: 0.77 [0.70-0.84]). This was an improvement of 0.17 [0.016-0.28] (p = 0.004). CONCLUSIONS: A dedicated teaching course on the use of the PRECISE score improves the accuracy in the assessment of radiological change in serial MRI of the prostate.
RESUMEN
Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic ß-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2-expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.
Asunto(s)
Interleucina-2/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Linfocitos T Reguladores/metabolismoRESUMEN
The role of interleukin-1 in the regulation of humoral responses is poorly documented, in contrast to its role in inflammation. Recent findings suggest there is an interleukin-1 axis in the follicular T cell control of B cell responses, involving interleukin-1 receptors (IL-1R1 and IL-1R2) and receptor antagonists (IL-1Ra). Here, we revisit the literature on this topic and conclude that targeting the interleukin-1 pathway should be a valuable therapeutic approach in many diseases involving excessive production of (auto)antibodies, such as autoimmune diseases or allergy.
Asunto(s)
Interleucina-1/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Enfermedades Autoinmunes/inmunología , Humanos , Hipersensibilidad/inmunología , Inmunidad Humoral , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Transducción de SeñalRESUMEN
We report the case of a patient with a very profound CD4 T cell lymphopenia <20 cells/mm3 in the context of a primary HIV-1 infection, associated with both delayed HIV-specific antibody and CD8 T cell responses. A long-term immune reconstitution was observed after immediate initiation of antiretroviral therapy.
Asunto(s)
Linfocitos T CD4-Positivos , Infecciones por VIH/inmunología , Seronegatividad para VIH/inmunología , VIH-1 , Linfopenia/etiología , Viremia/inmunología , Western Blotting , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos , Candidiasis Bucal/etiología , Candidiasis Bucal/inmunología , Ensayo de Inmunoadsorción Enzimática , Reacciones Falso Negativas , Femenino , Francia , Genotipo , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/sangre , Seropositividad para VIH , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Linfopenia/sangre , Linfopenia/inmunología , Persona de Mediana Edad , Nigeria/etnología , Precursores de Proteínas/sangre , Viremia/sangreRESUMEN
Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25+ cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25-, in mice and humans. Moreover, Tfr cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25+ cells resulted in contamination with Treg cells. Transcriptome studies of CD4+CXCR5+PD-1+Bcl6+Foxp3+CD25- Tfr cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas Tfh cells express the IL-1R1 agonist receptor. IL-1 treatment expanded Tfh cells in vivo and activated their production of IL-4 and IL-21 in vitro. Tfr cells suppressed the IL-1-induced activation of Tfh cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the Tfh cell control of B cell responses and an IL-2/IL-1 dichotomy for Treg cell control of effector T cells versus Tfr cell control of Tfh cells.