Catálogo de publicaciones - libros

The B cell developmental pathway represents a leading system for the analysis of regulatory circuits that orchestrate cell fate specification, commitment, and differentiation. We review the progress that has been achieved in the identification and characterization of regulatory components of such circuits, including transcription factors, chromatin modifying proteins, and signaling molecules. A comprehensive developmental model is proposed that invokes sequentially acting regulatory networks which dictate the generation of B cells from multipotential hematopoietic progenitors.

The cells of the lymphoid system develop from multipotent hematopoietic stem cells through a series of intermediate progenitors with progressively restricted developmental options. Commitment to a given lymphoid lineage appears to be controlled by numerous transcriptional regulatory proteins that activate lineage-specific gene expression programs and extinguish expression of lineage-inappropriate genes. In this review I discuss the function of transcription factors belonging to the helix-loop-helix protein family in the control of lymphoid cell fate decisions. A model of lymphocyte lineage determination based on the antagonistic activity of transcriptional activating and repressing helix-loop-helix proteins is presented.

The regulatory steps that lead to the differentiation of hematopoietic cells from a multipotential stem cell remain largely unknown. A beginning to the understanding of these steps has come from the study of DNA-binding proteins that are thought to regulate the expression of genes required for specific developmental events. Ikaros is the founding member of a small family of DNA-binding proteins required for lymphocyte development, but the members of this family differ from other key regulators of lymphopoiesis in that direct target genes have not been conclusively identified, and reasonable support has been presented for only a few potential targets. Therefore, the molecular mechanisms that Ikaros uses for regulating lymphocyte development remain largely unknown. Current data suggest that, in some instances, Ikaros may function as a typical transcription factor. However, recent results suggest that it may function more broadly, perhaps in the formation of silent and active chromatin structures. In this review, our current knowledge of the molecular functions of Ikaros will be discussed.

The genes that encode immunoglobulin and T cell receptor proteins are assembled from component gene segments in a reaction known as V(D)J recombination. The reaction, and its crucial mediators RAG1 and RAG2, are essential for lymphocyte development and hence for adaptive immunity. Here we consider the biochemistry of this reaction, focusing on the DNA transactions and the proteins involved. We discuss how the RAG proteins interact with DNA and how coordinate cleavage of the DNA at two sites might be achieved. Finally, we consider the RAG proteins and V(D)J recombination from an evolutionary point of view.

B cell development is a process tightly regulated by the orchestrated signaling of cytokine receptors, the pre-B cell receptor (BCR) and the B cell receptor (BCR). It commences with common lymphoid progenitors (CLP) up-regulating the expression of B cell-related genes and committing to the B cell lineage. Cytokine signaling (IL-7, stem cell factor, FLT3-L) is essential at this stage of development as it suppresses cell death, sustains proliferation and facilitates heavy chain rearrangements. As a result of heavy chain recombination, the pre-BCR is expressed, which then becomes the primary determiner of survival, cell cycle entry and allelic exclusion. In this review, we discuss the mechanisms of B cell lineage commitment and describe the signaling pathways that are initiated by the pre-BCR. Finally, we compare pre-BCR and pre-TCR structure, signal transduction and function, drawing parallels between early pre-B and pre-T cell development.

The developmental program that commits a hematopoietic stem cell to the B lymphocyte lineage employs transcriptional regulators to enable the assembly of an antigen receptor complex with a useful specificity and with signalling competence. Once a naive IgM^+ B cell is generated, it must correctly integrate signals from the antigen receptor with those from cytokine receptors and co-receptors delivering T cell help. The B cell responds through the regulated expression of genes that implement specific cell expansion and differentiation, secretion of high levels of high-affinity antibody, and generation of long-term memory. The transcriptional regulators highlighted in this chapter are those for which genetic evidence of function in IgM^+ B cells in vivo has been provided, often in the form of mutant mice generated by conventional or conditional gene targeting. A critical developmental step is the maturation of bone marrow emigrant “transitional” B cells into the mature, long-lived cells of the periphery, and a number of the transcription factors discussed here impact on this process, yielding B cells with poor mitogenic responses in vitro. For mature B cells, it is clear that not only the nature, but the duration and amplitude of an activating signal are major determinants of the transcription factor activities enlisted, and so the ultimate outcome. The current challenge is the identification of the target genes that are activated to implement the correct response, so that we may more precisely and safely manipulate B cell behavior to predictably and positively influence humoral immune responses.

Innate and adaptive immunity are connected via antigen processing and presentation (APP), which results in the presentation of antigenic peptides to T cells in the complex with the major histocompatibility (MHC) determinants. MHC class II (MHC II) determinants present antigens to CD4^+ T cells, which are the main regulators of the immune response. Their genes are transcribed from compact promoters that form first the MHC II enhanceosome, which contains DNA-bound activators and then the MHC II transcriptosome with the addition of the class II transactivator (CIITA). CIITA is the master regulator of MHC II transcription. It is expressed constitutively in dendritic cells (DC) and mature B cells and is inducible in most other cell types. Three isoforms of CIITA exist, depending on cell type and inducing signals. CIITA is regulated at the levels of transcription and post-translational modifications, which are still not very clear. Inappropriate immune responses are found in several diseases, including cancer and autoimmunity. Since CIITA regulates the expression of MHC II genes, it is involved directly in the regulation of the immune response. The knowledge of CIITA will facilitate the manipulation of the immune response and might contribute to the treatment of these diseases.

Class switch recombination (CSR) has been the least well understood of the Ig gene DNA rearrangements. The discovery that activation-induced deaminase (AID) is a pivotal player in CSR as well as somatic hypermutation (SHM) and its variant, gene conversion, represents a sea change in our understanding of these processes. The recognition that AID directly deaminates ssDNA has provided a springboard toward the emergence of a model that explains the initiation of these events. Nonhomologous end joining (NHEJ), the main pathway for the repair of double-strand breaks in mammalian cells plays a key role in the resolution of CSR transactions. Mediators of general double-strand break repair are also involved in CSR and are mutated in several immunodeficiency diseases. A global picture of the mechanism of CSR is emerging and is providing new insights toward understanding the genetic events that underlie B cell cancers.

The transcription factor Blimp-1 governs the generation of plasma cells and immunoglobulin secretion. Recent microarray experiments indicate that Blimp-1 regulates a large set of genes that constitute a significant part of the plasma cell expression signature. The variety of differentially expressed genes indicates that Blimp-1 affects numerous aspects of plasma cell maturation, ranging from migration, adhesion, and homeostasis, to antibody secretion. In addition, Blimp-1 regulates immunoglobulin secretion by affecting the nuclear processing of the mRNA transcript and by affecting protein trafficking by regulating genes that impact on the activity of the endoplasmic reticulum. Interestingly, the differentiation events that Blimp-1 regulates appear to be modulated depending on the activation state of the B cell. This modulation may be due at least in part to distinct regions of Blimp-1 that regulate unique sets of genes independently of each other. These data hint at the complexity of Blimp-1 and the genetic program that it initiates to produce a pool of plasma cells necessary for specific immunity.

Wnt signaling elicits changes in gene expression and cell physiology through β -catenin and LEF1/TCF proteins. The signal transduction pathway regulates many cellular and developmental processes, including cell proliferation, cell fate decisions and differentiation. In cells that have been stimulated by a Wnt protein, cytoplasmic β -catenin is stabilized and transferred to the nucleus, where it interacts with the nuclear mediators of Wnt signaling, the LEF1/TCF proteins, to elicit a transcriptional response. Loss-of-function and gain-of-function experiments in the mouse have provided insight into the role of this signaling pathway in lymphopoiesis. The self-renewal and maintenance of hematopoietic stem cells is regulated by Wnt signals. Differentiation of T cells and natural killer cells is blocked in the absence of LEF1/TCF proteins, and pro-B cell proliferation is regulated by Wnt signaling.