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1.
Nat Methods ; 15(8): 623-630, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30065364

RESUMEN

Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2-/-Il2rg-/-SirpaNOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (TFH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN TFH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.


Asunto(s)
Ganglios Linfáticos/crecimiento & desarrollo , Ganglios Linfáticos/inmunología , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Citocinas/genética , Citocinas/inmunología , Femenino , Infecciones por VIH/inmunología , VIH-1 , Humanos , Cambio de Clase de Inmunoglobulina , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Ganglios Linfáticos/citología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Inmunológicos , Linfocitos T/citología , Linfocitos T/inmunología , Latencia del Virus/inmunología , Linfopoyetina del Estroma Tímico
2.
J Immunol ; 200(10): 3519-3529, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29632141

RESUMEN

HIV-1 infection is associated with B cell dysregulation and dysfunction. In HIV-1-infected patients, we previously reported preservation of intestinal lymphoid structures and dendritic cell maturation pathways after early combination antiretroviral therapy (e-ART), started during the acute phase of the infection, compared with late combination antiretroviral therapy started during the chronic phase. In this study, we investigated whether the timing of combination antiretroviral therapy initiation was associated with the development of the HIV-1-specific humoral response in the gut. The results showed that e-ART was associated with higher frequencies of functional resting memory B cells in the gut. These frequencies correlated strongly with those of follicular Th cells in the gut. Importantly, frequencies of HIV-1 Env gp140-reactive B cells were higher in patients given e-ART, in whom gp140-reactive IgG production by mucosal B cells increased after stimulation. Moreover, IL-21 release by PBMCs stimulated with HIV-1 peptide pools was greater with e-ART than with late combination antiretroviral therapy. Thus, early treatment initiation helps to maintain HIV-1-reactive memory B cells in the gut as well as follicular Th cells, whose role is crucial in the development of potent affinity-matured and broadly neutralizing Abs.


Asunto(s)
Antirretrovirales/uso terapéutico , Linfocitos B/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Adulto , Anciano , Linfocitos B/virología , Femenino , Humanos , Memoria Inmunológica/efectos de los fármacos , Interleucinas/metabolismo , Mucosa Intestinal/virología , Intestinos/virología , Masculino , Persona de Mediana Edad , Linfocitos T Colaboradores-Inductores/virología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo
3.
Eur J Immunol ; 46(10): 2340-2351, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27469325

RESUMEN

Class-switched memory B cells are key components of the "reactive" humoral immunity, which ensures a fast and massive secretion of high-affinity antigen-specific antibodies upon antigenic challenge. In humans, IgA class-switched (IgA+ ) memory B cells and IgA antibodies are abundant in the blood. Although circulating IgA+ memory B cells and their corresponding secreted immunoglobulins likely possess major protective and/or regulatory immune roles, little is known about their specificity and function. Here, we show that IgA+ and IgG+ memory B-cell antibodies cloned from the same healthy humans share common immunoglobulin gene features. IgA and IgG memory antibodies have comparable lack of reactivity to vaccines, common mucosa-tropic viruses and commensal bacteria. However, the IgA+ memory B-cell compartment contains fewer polyreactive clones and importantly, only rare self-reactive clones compared to IgG+ memory B cells. Self-reactivity of IgAs is acquired following B-cell affinity maturation but not antibody class switching. Together, our data suggest the existence of different regulatory mechanisms for removing autoreactive clones from the IgG+ and IgA+ memory B-cell repertoires, and/or different maturation pathways potentially reflecting the distinct nature and localization of the cognate antigens recognized by individual B-cell populations.


Asunto(s)
Diversidad de Anticuerpos , Autoanticuerpos/metabolismo , Linfocitos B/fisiología , Inmunoglobulina A/metabolismo , Memoria Inmunológica , Afinidad de Anticuerpos , Formación de Anticuerpos , Autoantígenos/metabolismo , Autoinmunidad , Selección Clonal Mediada por Antígenos , Células Clonales , Humanos , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/metabolismo , Análisis de la Célula Individual
4.
PLoS Pathog ; 9(4): e1003319, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23658513

RESUMEN

The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39-. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.


Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Infecciones por VIH/inmunología , Interleucina-2/biosíntesis , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Anticuerpos Monoclonales/inmunología , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Apirasa/biosíntesis , Apirasa/inmunología , Proliferación Celular , AMP Cíclico/metabolismo , Metilación de ADN , VIH-1/inmunología , Humanos , Interleucina-2/genética , Activación de Linfocitos , Regiones Promotoras Genéticas , Receptor de Adenosina A2A/metabolismo , Subgrupos de Linfocitos T/metabolismo
5.
J Infect Dis ; 209(9): 1321-30, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24357632

RESUMEN

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by chronic immune activation and suppressed T-lymphocyte functions. Here we report that CD73, both a coactivator molecule of T cells and an immunosuppressive ecto-enzyme through adenosine production, is only weakly expressed by CD8+ T cells of HIV-infected patients and only partially restored after successful antiviral treatment. CD73 expression on CD8+ T cells correlates inversely with cell activation both ex vivo and in vitro. However, CD8+ T cells from HIV controllers (HICs), which spontaneously control HIV replication, express CD73 strongly, despite residual immune activation. Finally, we demonstrate that CD73 is involved in the HIV-specific CD8+ T-cell expansion. Thus, we show that CD73 is central to the functionality of HIV-specific CD8+ T cells and that the preservation of HIV-specific CD73+ CD8+ T cells is a characteristic of HICs. These observations reveal a novel mechanism involved in the control of viral replication.


Asunto(s)
5'-Nucleotidasa/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , 5'-Nucleotidasa/sangre , Linfocitos T CD8-positivos/citología , Estudios de Casos y Controles , Proteínas Ligadas a GPI/sangre , Proteínas Ligadas a GPI/inmunología , Infecciones por VIH/sangre , Interacciones Huésped-Patógeno/inmunología , Humanos
6.
PLoS Pathog ; 7(7): e1002110, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21750674

RESUMEN

HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25(high) FoxP3+CD127(low) T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS.


Asunto(s)
Adenosina/inmunología , Antígenos CD/inmunología , Apirasa/inmunología , Infecciones por VIH/inmunología , Linfocitos T Reguladores/inmunología , Adenosina/metabolismo , Antígenos CD/metabolismo , Apirasa/metabolismo , Biomarcadores/metabolismo , Bulgaria/epidemiología , Proliferación Celular , Células Cultivadas , Progresión de la Enfermedad , Regulación hacia Abajo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Francia/epidemiología , Expresión Génica , Infecciones por VIH/metabolismo , Infecciones por VIH/mortalidad , Humanos , Activación de Linfocitos , Polimorfismo Genético , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Tasa de Supervivencia , Linfocitos T Reguladores/metabolismo
7.
Cell Rep ; 27(2): 572-585.e7, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30970259

RESUMEN

Mucosal immune responses to HIV-1 involve the recognition of the viral envelope glycoprotein (gp)160 by tissue-resident B cells and subsequent secretion of antibodies. To characterize the B cells "sensing" HIV-1 in the gut of infected individuals, we probed monoclonal antibodies produced from single intestinal B cells binding to recombinant gp140 trimers. A large fraction of mucosal B cell antibodies were polyreactive and showed only low affinity to HIV-1 envelope glycoproteins, particularly the gp41 moiety. A few high-affinity gp140 antibodies were isolated but lacked neutralizing, potent ADCC, and transcytosis-blocking capacities. Instead, they displayed cross-reactivity with defined self-antigens. Specifically, intestinal HIV-1 gp41 antibodies targeting the heptad repeat 2 region (HR2) cluster II cross-reacted with the p38α mitogen-activated protein kinase 14 (MAPK14). Hence, physiologic polyreactivity of intestinal B cells and molecular mimicry-based self-reactivity of HIV-1 antibodies are two independent phenomena, possibly diverting and/or impairing mucosal humoral immunity to HIV-1.


Asunto(s)
Linfocitos B/inmunología , Reacciones Cruzadas/inmunología , VIH-1/inmunología , Intestinos/fisiopatología , Humanos
8.
Cell Rep ; 23(9): 2568-2581, 2018 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-29847789

RESUMEN

Human high-affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Here, we report that HIV-1 broadly neutralizing antibodies (bNAbs) are frequently polyreactive, cross-reacting with non-HIV-1 molecules, including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also results in de novo polyreactivity. Unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibit a conformational flexibility, which contributes to enhanced affinity of bNAbs to various HIV-1 envelope glycoproteins and non-HIV antigens. Binding adaptation of polyreactive bNAbs to the divergent ligands mainly involves hydrophophic interactions. Plasticity of bNAbs' paratopes may, therefore, facilitate accommodating divergent viral variants, but it simultaneously triggers promiscuous binding to non-HIV-1 antigens. Thus, a certain level of polyreactivity can be a mark of adaptable antibodies displaying optimal pathogens' recognition.


Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Autoantígenos/inmunología , Sitios de Unión de Anticuerpos , Reacciones Cruzadas/inmunología , Antígenos VIH/inmunología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Fragmentos Fab de Inmunoglobulinas/inmunología , Pruebas de Neutralización , Conformación Proteica , Termodinámica , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo
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