RESUMEN
Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease.
Asunto(s)
Culicidae/inmunología , Interacciones Huésped-Patógeno/inmunología , Malaria/inmunología , Plasmodium/inmunología , Animales , Culicidae/parasitología , Humanos , Estadios del Ciclo de Vida , Malaria/parasitología , Malaria/prevención & control , Plasmodium/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/inmunologíaRESUMEN
All vaccines rely on the ability of B cells to remember pathogen infections and respond more vigorously upon reinfection. In this issue of Cell, Viant et al. address the real-world issue of protection against rapidly emerging pathogen variants and describe how memory B cells may anticipate infections by such variants.
Asunto(s)
Memoria Inmunológica , Vacunas , Afinidad de Anticuerpos , Linfocitos B , Centro GerminalRESUMEN
Women have been at the forefront of tremendous achievements in immunology in the past decade. However, disparities still exist, limiting upward potential and further advancements. As four NIH intramural women scientists who care deeply about scientific progress and the progress of women in our field, we review ongoing challenges and discuss potential approaches to help advance the promotion of women in the sciences.
Asunto(s)
Alergia e Inmunología/tendencias , Sexismo/tendencias , Derechos de la Mujer/tendencias , Investigación Biomédica/tendencias , Movilidad Laboral , Femenino , Historia del Siglo XXI , Humanos , Tutoría/tendencias , National Institutes of Health (U.S.) , Estados UnidosRESUMEN
Over the past several decades, B cell antigen receptor (BCR)-induced signaling pathways have been described in extraordinary molecular detail, mainly from studies of B cell responses to antigens in vitro. BCR signaling has been shown to govern the initiation of transcriptional programs associated with B cell activation and fate decisions, as well as the BCR-dependent processing of antigen and presentation of antigen to T cells. However, although the potential of the BCR to orchestrate B cell behavior was known, there was no clear appreciation of the context in which B cells signal in secondary lymphoid organs in vivo or how that context influences signaling. In this Review, we describe the current view of the cellular consequences of BCR signaling and advances in the understanding of B cell signaling in context in vivo.
Asunto(s)
Presentación de Antígeno/inmunología , Antígenos/inmunología , Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Humanos , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunologíaRESUMEN
B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absence of a second signal, B cells progressively lost mitochondrial function and glycolytic capacity, which led to apoptosis. Mitochondrial dysfunction was a result of the gradual accumulation of intracellular calcium through calcium response-activated calcium channels that, for approximately 9 h after the binding of B cell antigens, was preventable by either helper T cells or signaling via the receptor TLR9. Thus, BCR signaling seems to activate a metabolic program that imposes a limited time frame during which B cells either receive a second signal and survive or are eliminated.
Asunto(s)
Linfocitos B/fisiología , Mitocondrias/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Receptor Toll-Like 9/metabolismo , Animales , Apoptosis , Calcio/metabolismo , Canales de Calcio/metabolismo , Citocinas/metabolismo , Glucólisis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células 3T3 NIH , Fosforilación Oxidativa , Receptores de Antígenos de Linfocitos B/genética , Transducción de Señal , Receptor Toll-Like 9/genéticaRESUMEN
Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial, the TLR9 agonist CpG enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation. Thus, TLR9 signaling might enhance antibody titers at the expense of the ability of B cells to engage in germinal-center events that are highly dependent on B cells' capture and presentation of antigen.
Asunto(s)
Formación de Anticuerpos/inmunología , Presentación de Antígeno/genética , Activación de Linfocitos/inmunología , Receptor Toll-Like 9/inmunología , Animales , Afinidad de Anticuerpos , Centro Germinal/inmunología , Humanos , Vacunas contra la Malaria , Ratones , Receptor Toll-Like 9/agonistasRESUMEN
Immunoglobulin G3 (IgG3) has an uncertain role in the response to infection with and vaccination against human immunodeficiency virus (HIV). Here we describe a regulatory role for IgG3 in dampening the immune system-activating effects of chronic HIV viremia on B cells. Secreted IgG3 was bound to IgM-expressing B cells in vivo in HIV-infected chronically viremic individuals but not in early-viremic or aviremic individuals. Tissue-like memory (TLM) B cells, a population expanded by persistent HIV viremia, bound large amounts of IgG3. IgG3 induced clustering of B cell antigen receptors (BCRs) on the IgM+ B cells, which was mediated by direct interactions between soluble IgG3 and membrane IgM of the BCR (IgM-BCR). The inhibitory IgG receptor CD32b (FcγRIIb), complement component C1q and inflammatory biomarker CRP contributed to the binding of secreted IgG3 onto IgM-expressing B cells of HIV-infected individuals. Notably, IgG3-bound TLM B cells were refractory to IgM-BCR stimulation, thus demonstrating that IgG3 can regulate B cells during chronic activation of the immune system.
Asunto(s)
Linfocitos B/inmunología , Infecciones por VIH/inmunología , VIH-1/fisiología , Inmunoglobulina G/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Adulto , Proteína C-Reactiva/metabolismo , Células Cultivadas , Complemento C1q/metabolismo , Femenino , Humanos , Inmunoglobulina M/metabolismo , Memoria Inmunológica , Inmunomodulación , Masculino , Persona de Mediana Edad , Unión Proteica , Agregación de Receptores , Receptores de IgG/metabolismo , Adulto JovenRESUMEN
Memory B cells (MBCs) play a critical role in protection against homologous and variant pathogen challenge by either differentiating to plasma cells (PCs) or to germinal center (GC) B cells. The human MBC compartment contains both switched IgG+ and unswitched IgM+ MBCs; however, whether these MBC subpopulations are equivalent in their response to B cell receptor cross-linking and their resulting fates is incompletely understood. Here, we show that IgG+ and IgM+ MBCs can be distinguished based on their response to κ-specific monoclonal antibodies of differing affinities. IgG+ MBCs responded only to high-affinity anti-κ and differentiated almost exclusively toward PC fates. In contrast, IgM+ MBCs were eliminated by apoptosis by high-affinity anti-κ but responded to low-affinity anti-κ by differentiating toward GC B cell fates. These results suggest that IgG+ and IgM+ MBCs may play distinct yet complementary roles in response to pathogen challenge ensuring the immediate production of high-affinity antibodies to homologous and closely related challenges and the generation of variant-specific MBCs through GC reactions.
Asunto(s)
Cambio de Clase de Inmunoglobulina , Células B de Memoria , Humanos , Linfocitos B , Antígenos , Inmunoglobulina G , Inmunoglobulina M , Memoria InmunológicaRESUMEN
How early interactions between innate and adaptive immune cells influence outcomes of acute infections is incompletely understood. In this issue of Immunity, Karunarathne et al. (2016) show that dendritic cells help CD4(+) T helper 1 cell immunity against malaria through PD-L2's competition with PD-L1.
Asunto(s)
Antígeno B7-H1/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1 , Células Dendríticas/inmunología , Humanos , Activación de Linfocitos/inmunología , MalariaRESUMEN
Binding of antigen to the B cell antigen receptor (BCR) triggers both BCR signaling and endocytosis. How endocytosis regulates BCR signaling remains unknown. Here we report that BCR signaling was not extinguished by endocytosis of BCRs; instead, BCR signaling initiated at the plasma membrane continued as the BCR trafficked intracellularly with the sequential phosphorylation of kinases. Blocking the endocytosis of BCRs resulted in the recruitment of both proximal and downstream kinases to the plasma membrane, where mitogen-activated protein kinases (MAPKs) were hyperphosphorylated and the kinase Akt and its downstream target Foxo were hypophosphorylated, which led to the dysregulation of gene transcription controlled by these pathways. Thus, the cellular location of the BCR serves to compartmentalize kinase activation to regulate the outcome of signaling.
Asunto(s)
Linfocitos B/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Compartimento Celular/inmunología , Células Cultivadas , Endocitosis/inmunología , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Fosforilación/inmunología , Transporte de Proteínas/inmunología , Proteínas Proto-Oncogénicas c-akt/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/inmunología , Activación Transcripcional/inmunologíaRESUMEN
T cells exposed to persistent antigen in the inflammatory environment of chronic infections often show progressive loss of effector functions, high expression of inhibitory receptors and distinct transcriptional programs. T cells in this functional state are termed "exhausted" and T cell exhaustion is associated with inefficient control of infections. A remarkably similar scenario has been described for B cells during chronic infections in humans, including malaria, in which case a subpopulation of atypical memory B cells (MBCs) greatly expands and these MBCs show attenuation of B cell receptor signaling, loss of the B cell effector functions of antibody and cytokine production, high expression of inhibitory receptors and distinct transcriptional profiles. The expansion of these MBCs is also associated with inefficient control of infections. Despite the similarities with exhausted T cells we speculate that at least in malaria, atypical MBCs may not be exhausted but rather may be functional, possibly even beneficial. Our recent results suggest that we simply may not have known how to ask an atypical MBC to function. Thus, exhaustion may not be in the human B cell's vocabulary, at least not in malaria.
Asunto(s)
Antígenos de Protozoos/inmunología , Linfocitos B/inmunología , Memoria Inmunológica/inmunología , Malaria/inmunología , Linfocitos T/inmunología , Animales , Linfocitos B/metabolismo , Linfocitos B/parasitología , Humanos , Malaria/parasitología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal/inmunología , Linfocitos T/parasitologíaRESUMEN
Malaria is a deadly infectious disease caused by parasites of the Plasmodium spp. that takes an estimated 435,000 lives each year, primarily among young African children. For most children, malaria is a febrile illness that resolves with time, but in â¼1% of cases, for reasons we do not understand, malaria becomes severe and life threatening. Cerebral malaria (CM) is the most common form of severe malaria, accounting for the vast majority of childhood deaths from malaria despite highly effective antiparasite chemotherapy. Thus, CM is one of the most prevalent lethal brain diseases, and one for which we have no effective therapy. CM is, in part, an immune-mediated disease, and to fully understand CM, it is essential to appreciate the complex relationship between the malarial parasite and the human immune system. In this study, we provide a primer on malaria for immunologists and, in this context, review progress identifying targets for therapeutic intervention.
Asunto(s)
Malaria Cerebral/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood-brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.
Asunto(s)
Diazooxonorleucina/antagonistas & inhibidores , Diazooxonorleucina/uso terapéutico , Glutamina/antagonistas & inhibidores , Imagen por Resonancia Magnética/métodos , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/patología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/patología , Adulto , Animales , Antimaláricos/uso terapéutico , Biomarcadores , Barrera Hematoencefálica/patología , Encéfalo/parasitología , Encéfalo/patología , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/patología , Niño , Diazooxonorleucina/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Malaria Cerebral/diagnóstico por imagen , Malaria Cerebral/parasitología , Malaria Falciparum/diagnóstico por imagen , Ratones , Ratones Endogámicos C57BL , Plasmodium falciparum/patogenicidadRESUMEN
Activation of CD4+ T cells to proliferate drives cells toward aerobic glycolysis for energy production while using mitochondria primarily for macromolecular synthesis. In addition, the mitochondria of activated T cells increase production of reactive oxygen species, providing an important second messenger for intracellular signaling pathways. To better understand the critical changes in mitochondria that accompany prolonged T cell activation, we carried out an extensive analysis of mitochondrial remodeling using a combination of conventional strategies and a novel high-resolution imaging method. We show that for 4 d following activation, mouse CD4+ T cells sustained their commitment to glycolysis facilitated by increased glucose uptake through increased expression of GLUT transporters. Despite their limited contribution to energy production, mitochondria were active and showed increased reactive oxygen species production. Moreover, prolonged activation of CD4+ T cells led to increases in mitochondrial content and volume, in the number of mitochondria per cell and in mitochondrial biogenesis. Thus, during prolonged activation, CD4+ T cells continue to obtain energy predominantly from glycolysis but also undergo extensive mitochondrial remodeling, resulting in increased mitochondrial activity.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Mitocondrias/fisiología , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Animales , Células Cultivadas , Metabolismo Energético , Femenino , Glucólisis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de SeñalRESUMEN
Many chronic infections, including malaria and HIV, are associated with a large expansion of CD21-CD27- 'atypical' memory B cells (MBCs) that exhibit reduced B cell receptor (BCR) signaling and effector functions. Little is known about the conditions or transcriptional regulators driving atypical MBC differentiation. Here we show that atypical MBCs in malaria-exposed individuals highly express the transcription factor T-bet, and that T-bet expression correlates inversely with BCR signaling and skews toward IgG3 class switching. Moreover, a longitudinal analysis of a subset of children suggested a correlation between the incidence of febrile malaria and the expansion of T-bethi B cells. The Th1-cytokine containing supernatants of malaria-stimulated PBMCs plus BCR cross linking induced T-bet expression in naïve B cells that was abrogated by neutralizing IFN-γ or blocking the IFN-γ receptor on B cells. Accordingly, recombinant IFN-γ plus BCR cross-linking drove T-bet expression in peripheral and tonsillar B cells. Consistent with this, Th1-polarized Tfh (Tfh-1) cells more efficiently induced T-bet expression in naïve B cells. These data provide new insight into the mechanisms underlying atypical MBC differentiation.
Asunto(s)
Linfocitos B/citología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Regulación de la Expresión Génica/inmunología , Memoria Inmunológica/inmunología , Interferón gamma/biosíntesis , Malaria/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Proteínas Fetales/metabolismo , Humanos , Lactante , Malaria/metabolismo , Masculino , Receptores de Antígenos de Linfocitos B/metabolismo , Proteínas de Dominio T Box/metabolismo , Adulto JovenRESUMEN
Accumulating evidence suggests granulocyte macrophage-colony stimulating factor (GM-CSF) can function as an inflammatory mediator, but whether GM-CSF-producing CD4+ T cells (TH-GM-CSF) are a distinct T helper cell subset is lacking. Herein we demonstrate that interleukin (IL)-1ß exclusively drives differentiation of naïve CD4+ T cells into TH-GM-CSF cells via inducing ubiquitination of IL-1 receptor-associated kinase 1 (IRAK1) and subsequent activation of the transcription factor NF-kappaB (NF-κB), independent of RAR-related orphan receptor gamma (RORγt) required for TH17 differentiation. In vivo, TH-GM-CSF cells are present in murine Citrobacter Rodentium infections and mediate colitis following adoptive transfer of CD4+ T cells into Rag1-/- mice via GM-CSF-induced macrophage activation. The TH-GM-CSF cell phenotype is stable and distinct from the TH17 genetic program, but IL-1ß can convert pre-formed TH17â¯cells into TH-GM-CSF cells, thereby accounting for previously reported associations between IL-17 and GM-CSF. Together, our results newly identify IL-1ß/NF-κB-dependent TH-GM-CSF cells as a unique T helper cell subset and highlight the importance of CD4+ T cell-derived GM-CSF induced macrophage activation as a previously undescribed T cell effector mechanism.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Interleucina-1beta/inmunología , Activación de Macrófagos/inmunología , Células Th17/citología , Células Th17/inmunología , Animales , Diferenciación Celular/inmunología , Citrobacter rodentium/inmunología , Colitis/inmunología , Inflamación/inmunología , Inflamación/patología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/patología , UbiquitinaciónRESUMEN
Memory B cells express high-affinity, immunoglobulin GB cell receptors (IgG BCRs) that enhance B cell responses, giving rise to the rapid production of high-affinity, IgG antibodies. Despite the central role of IgG BCRs in memory responses, the mechanisms by which the IgG BCRs function to enhance B cell responses are not fully understood. Using high-resolution live-cell imaging, we showed that IgG1 BCRs dramatically enhanced the earliest BCR-intrinsic events that followed within seconds of B cells' encounter with membrane bound antigen, including BCR oligomerization and BCR microcluster growth, leading to Syk kinase recruitment and calcium responses. The enhancement of these early events was dependent on a membrane proximal region of the IgG1 cytoplasmic tail not previously appreciated to play a role in IgG1 BCR signaling. Thus, intrinsic properties of the IgG1 BCR enhance early antigen-driven events that ultimately translate into heightened signaling.
Asunto(s)
Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/inmunología , Animales , Calcio/inmunología , Calcio/metabolismo , Membrana Celular/inmunología , Membrana Celular/metabolismo , Inmunoglobulina G/metabolismo , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Tirosina Quinasas/inmunología , Proteínas Tirosina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Quinasa Syk , TransfecciónRESUMEN
B cells express the innate receptor, TLR9, which signals in response to unmethylated CpG sequences in microbial DNA. Of the two major classes of CpG-containing oligonucleotides, CpG-A appears restricted to inducing type 1 IFN in innate immune cells and CpG-B to activating B cells to proliferate and produce Abs and inflammatory cytokines. Although CpGs are candidates for adjuvants to boost innate and adaptive immunity, our understanding of the effect of CpG-A and CpG-B on B cell responses is incomplete. In this study we show that both CpG-B and CpG-A activated B cells in vitro to proliferate, secrete Abs and IL-6, and that neither CpG-B nor CpG-A alone induced type 1 IFN production. However, when incorporated into the cationic lipid, DOTAP, CpG-A, but not CpG-B, induced a type 1 IFN response in B cells in vitro and in vivo. We provide evidence that differences in the function of CpG-A and CpG-B may be related to their intracellular trafficking in B cells. These findings fill an important gap in our understanding of the B cell response to CpGs, with implications for the use of CpG-A and CpG-B as immunomodulators.
Asunto(s)
Linfocitos B/inmunología , Interferón Tipo I/biosíntesis , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/inmunología , Animales , Formación de Anticuerpos , Linfocitos B/efectos de los fármacos , Cationes/inmunología , Citocinas/genética , Citocinas/inmunología , Inmunidad Innata , Factores Inmunológicos/metabolismo , Interferón Tipo I/inmunología , Interleucina-6/biosíntesis , Interleucina-6/inmunología , Lípidos/administración & dosificación , Lípidos/química , Lípidos/farmacología , Activación de Linfocitos , Ratones , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/farmacología , Receptor Toll-Like 9/agonistasRESUMEN
The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP. We provide evidence that only NP-CGG adjuvanted with DOTAP-CpG-B was an effective vaccine in mice resulting in robust germinal center responses, isotype switching and high affinity NP-specific antibodies. The effectiveness of DOTAP-CpG-B as an adjuvant was dependent on the expression of the TLR9 signaling adaptor MyD88 in immunized mice. These results indicate DOTAP-CpG-B but not DOTAP-CpG-A is an effective adjuvant for T cell-dependent protein antigen-based vaccines.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Ácidos Grasos Monoinsaturados/farmacología , Oligodesoxirribonucleótidos/inmunología , Compuestos de Amonio Cuaternario/farmacología , Linfocitos T/inmunología , Vacunas/inmunología , Animales , Afinidad de Anticuerpos , Ácidos Grasos Monoinsaturados/inmunología , Centro Germinal/inmunología , Ratones , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/farmacología , Compuestos de Amonio Cuaternario/inmunología , Vacunas/farmacologíaRESUMEN
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature.