RESUMEN
B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Receptores de Células Precursoras de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Diferenciación Celular/genética , Inmunoglobulina de Cadenas Ligeras Subrogadas/genética , Inmunoglobulina de Cadenas Ligeras Subrogadas/inmunología , Inmunoglobulina de Cadenas Ligeras Subrogadas/metabolismo , Hígado/embriología , Hígado/inmunología , Hígado/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Células Precursoras de Linfocitos B/genética , Receptores de Células Precursoras de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Receptores de Interleucina-7/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Factor de Transcripción STAT5/metabolismoRESUMEN
B-1a cells remain one of the most enigmatic lymphocyte subsets. In this review, we discuss recent advances in our understanding of the development of these cells and their regulation by the transcription factors Bhlhe41 and Arid3a as well as by the RNA-binding protein Lin28b. A large body of literature supports an instructive role of BCR signaling in B-1a cell development and lineage commitment, which is initiated only after signaling from an autoreactive BCR. While both fetal and adult hematopoiesis can generate B-1a cells, the contribution of adult hematopoiesis to the B-1a cell compartment is low under physiological conditions. We discuss several models that can reconcile the instructive role of BCR signaling with this fetal bias in B-1a cell development.
Asunto(s)
Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/metabolismo , Diferenciación Celular , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Animales , Subgrupos de Linfocitos B/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula , Selección Clonal Mediada por Antígenos , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Reordenamiento Génico de Linfocito B/genética , Reordenamiento Génico de Linfocito B/inmunología , Humanos , Inmunoglobulinas/genéticaRESUMEN
Many DNA lesions associated with lymphoid malignancies are linked to off-target cleavage by the RAG1/2 recombinase. However, off-target cleavage has mostly been analyzed in the context of DNA repair defects, confounding any mechanistic understanding of cleavage deregulation. We identified a conserved SQ phosphorylation site on RAG2 365 to 366 that is involved in feedback control of RAG cleavage. Mutation of serine 365 to a non-phosphorylatable alanine permits bi-allelic and bi-locus RAG-mediated breaks in the same cell, leading to reciprocal translocations. This phenomenon is analogous to the phenotype we described for ATM kinase inactivation. Here, we establish deregulated cleavage itself as a driver of chromosomal instability without the associated repair defect. Intriguingly, a RAG2-S365E phosphomimetic rescues the deregulated cleavage of ATM inactivation, reducing the incidence of reciprocal translocations. These data support a model in which feedback control of cleavage and maintenance of genome stability involves ATM-mediated phosphorylation of RAG2.
