Advances In Immunology[JOURNAL]
Sun
200 papers
Combinatorial Cancer Immunotherapies.
Hellmann MD, Friedman CF, Wolchok JD
Adv Immunol · 2016 · PMID 26923003 · Publisher ↗
T cell checkpoint blockade therapies are revolutionizing the treatment of patients with cancer. Highlighted by the recent success of PD-1 plus CTLA-4 blockade in patients with melanomas, synergistic immunotherapy combina...
T cell checkpoint blockade therapies are revolutionizing the treatment of patients with cancer. Highlighted by the recent success of PD-1 plus CTLA-4 blockade in patients with melanomas, synergistic immunotherapy combinations of modalities represent an important opportunity to improve responses and outcomes for patients. We review the rationale and experience with T cell checkpoint blockade in combination with targeting of other coinhibitory or costimulatory checkpoints, immunomodulatory molecules in the tumor microenvironment, and other anticancer modalities such as vaccines, chemotherapy, and radiation.
Advances in Therapeutic Cancer Vaccines.
Wong KK, Li WA, Mooney DJ … +1 more , Dranoff G
Adv Immunol · 2016 · PMID 26923002 · Publisher ↗
Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explore...
Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines.
Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers.
Becht E, Giraldo NA, Germain C … +6 more , de Reyniès A, Laurent-Puig P, Zucman-Rossi J, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH
Adv Immunol · 2016 · PMID 26923001 · Publisher ↗
The outcome of tumors results from genetic and epigenetic modifications of the transformed cells and also from the interactions of the malignant cells with their tumor microenvironment (TME), which includes immune and in...
The outcome of tumors results from genetic and epigenetic modifications of the transformed cells and also from the interactions of the malignant cells with their tumor microenvironment (TME), which includes immune and inflammatory cells. For a given cancer type, the composition of the immunological TME is not homogeneous. Heterogeneity is found between different cancer types and also between tumors from patients with the same type of cancer. Some tumors exhibit a poor infiltration by immune cells, and others are highly infiltrated by lymphocytes. Among the latter, the architecture of the TME, with the localization of immune cells in the invasive front and the center of the tumor, the presence of tumor-adjacent organized lymphoid aggregates, and the type of inflammatory context, determines the prognostic impact of the infiltrating cells. The description and the understanding of the immune and inflammatory landscape in human tumors are of paramount importance at different levels of patient's care. It completes the mutational, transcriptional, and epigenetic patterns of the malignant cells and open paths to understand how tumor cells shape their immune microenvironment and are shaped by the immune reaction. It provides prognostic and theranostic markers, as well as novel targets for immunotherapies.
Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy.
Spranger S, Sivan A, Corrales L … +1 more , Gajewski TF
Adv Immunol · 2016 · PMID 26923000 · Full text
Despite recent clinical advances in immunotherapy, a fraction of cancer patients fails to respond to these interventions. Evidence from preclinical mouse models as well as clinical samples has provided evidence that the...
Despite recent clinical advances in immunotherapy, a fraction of cancer patients fails to respond to these interventions. Evidence from preclinical mouse models as well as clinical samples has provided evidence that the extent of activated T cell infiltration within the tumor microenvironment is associated with clinical response to immunotherapies including checkpoint blockade. Therefore, understanding the molecular mechanisms mediating the lack of T cell infiltration into the tumor microenvironment will be instrumental for the development of new therapeutic strategies to render those patients immunotherapy responsive. Recent data have suggested that major sources of intersubject heterogeneity include differences in somatic mutations in specific oncogene pathways between cancers of individual subjects and also environmental factors including commensal microbial composition. Successful identification of such causal factors should lead to new therapeutic approaches that may facilitate T cell entry into noninflamed tumors and expand the fraction of patients capable of responding to novel immunotherapies.
The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer.
Ward JP, Gubin MM, Schreiber RD
Adv Immunol · 2016 · PMID 26922999 · Full text
Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity...
Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity on developing cancers. Tumor-specific neoantigens can serve as targets of spontaneously arising adaptive immunity to cancer and thereby determine the ultimate fate of developing tumors. Tumor-specific neoantigens can also function as optimal targets of cancer immunotherapy against established tumors. These antigens are derived from nonsynonymous mutations that occur during cellular transformation and, because they are foreign to the host genome, are not subject to central tolerance. In this review, we summarize the experimental evidence indicating that cancer neoantigens are the source of both spontaneously occurring and therapeutically induced immune responses against cancer. We also review the advances in genomics, bioinformatics, and cancer immunotherapy that have facilitated identification of neoantigens and have moved personalized cancer immunotherapies into clinical trials, with the promise of providing more specific, safer, more effective, and perhaps even more generalizable treatments to cancer patients than current immunotherapies.
Mouse Models of Tumor Immunotherapy.
Ngiow SF, Loi S, Thomas D … +1 more , Smyth MJ
Adv Immunol · 2016 · PMID 26922998 · Publisher ↗
Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of ac...
Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.
MAP4K Family Kinases in Immunity and Inflammation.
Chuang HC, Wang X, Tan TH
Adv Immunol · 2016 · PMID 26791862 · Publisher ↗
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been rep...
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been reported to induce JNK activation through activating the MAP3K-MAP2K cascade. The physiological roles of MAP4Ks in immunity and inflammation are largely unknown until recent studies using biochemical approaches and knockout mice. Surprisingly, JNK is not the major target of MAP4Ks in immune cells; MAP4Ks regulate immune responses through novel targets. HPK1 inhibits T-cell receptor (TCR) signaling and B-cell receptor signaling via inducing phosphorylation/ubiquitination of SLP-76 and BLNK, respectively. GLK activates TCR signaling through phosphorylating/activating PKCθ. T-cell-mediated immune responses and Th17-mediated experimental autoimmune diseases are enhanced in HPK1 knockout mice but ameliorated in GLK knockout mice. Consistently, HPK1 levels are decreased in peripheral blood mononuclear cells and T cells from patients with psoriatic arthritis and systemic lupus erythematosus (SLE), respectively. Moreover, GLK levels are increased in T cells from patients with SLE, rheumatoid arthritis, or adult-onset Still's disease; the percentages of GLK-overexpression T cells are correlated with the disease activity. In addition, HGK phosphorylates and induces TRAF2 protein degradation, leading to negative regulation of IL-6 production in resting T cells. Loss of HGK in T cells results in spontaneous systemic inflammation and type 2 diabetes in mice. HGK is also involved in cancer cell migration. To date, the phenotypes of knockout mice for GCK, KHS, and MINK have not been reported; the roles of these three MAP4Ks in immune cell signaling are discussed in this review. Taken together, MAP4K family kinases play diverse roles in immune cell signaling, immune responses, and inflammation.
The Pathogenesis and Immunobiology of Mousepox.
Sigal LJ
Adv Immunol · 2016 · PMID 26791861 · Publisher ↗
Ectromelia virus is a mouse-specific orthopoxvirus that, following footpad infection or natural transmission, causes mousepox in most strains of mice, while a few strains, such as C57BL/6, are resistant to the disease bu...
Ectromelia virus is a mouse-specific orthopoxvirus that, following footpad infection or natural transmission, causes mousepox in most strains of mice, while a few strains, such as C57BL/6, are resistant to the disease but not to the infection. Mousepox is an acute, systemic, highly lethal disease of remarkable semblance to smallpox, caused by the human-specific variola virus. Starting in 1929 with its discovery by Marchal, work with ECTV has provided essential information for our current understanding on how viruses spread lympho-hematogenously, the genetic control of antiviral resistance, the role of different components of the innate and adaptive immune system in the control of primary and secondary infections with acute viruses, and how the mechanisms of immune evasion deployed by the virus affect virulence in vivo. Here, I review the literature on the pathogenesis and immunobiology of ECTV infection in vivo.
Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.
Sasazuki T, Inoko H, Morishima S … +1 more , Morishima Y
Adv Immunol · 2016 · PMID 26791860 · Publisher ↗
The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes m...
The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure.
Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control.
Rothenberg EV, Ungerbäck J, Champhekar A
Adv Immunol · 2016 · PMID 26791859 · Full text
T-lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession...
T-lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of innate lymphoid cells (ILCs) that share transcriptional regulation programs extensively with T-cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate.
Evolution of the Humoral Response during HCV Infection: Theories on the Origin of Broadly Neutralizing Antibodies and Implications for Vaccine Design.
Murira A, Lapierre P, Lamarre A
Adv Immunol · 2016 · PMID 26791858 · Publisher ↗
Similar to human immunodeficiency virus (HIV)-1, vaccine-induced elicitation of broadly neutralizing (bNt) antibodies (Abs) is gaining traction as a key goal toward the eradication of the hepatitis C virus (HCV) pandemic...
Similar to human immunodeficiency virus (HIV)-1, vaccine-induced elicitation of broadly neutralizing (bNt) antibodies (Abs) is gaining traction as a key goal toward the eradication of the hepatitis C virus (HCV) pandemic. Previously, the significance of the Ab response against HCV was underappreciated given the prevailing evidence advancing the role of the cellular immune response in clearance and overall control of the infection. However, recent findings have driven growing interest in the humoral arm of the immune response and in particular the role of bNt responses due to their ability to confer protective immunity upon passive transfer in animal models. Nevertheless, the origin and development of bNt Abs is poorly understood and their occurrence is rare as well as delayed with emergence only observed in the chronic phase of infection. In this review, we characterize the interplay between the host immune response and HCV as it progresses from the acute to chronic phase of infection. In addition, we place these events in the context of current hypotheses on the origin of bNt Abs against the HIV-1, whose humoral immune response is better characterized. Based on the increasing significance of the humoral immune response against HCV, characterization of these events may be critical in understanding the development of the bNt responses and, thus, provide strategies toward effective vaccine design.
Mechanism of Diapedesis: Importance of the Transcellular Route.
Filippi MD
Adv Immunol · 2016 · PMID 26791857 · Full text
The neutrophil transmigration across the blood endothelial cell barrier represents the prerequisite step of innate inflammation. Neutrophil recruitment to inflamed tissues occurs in a well-defined stepwise manner, which...
The neutrophil transmigration across the blood endothelial cell barrier represents the prerequisite step of innate inflammation. Neutrophil recruitment to inflamed tissues occurs in a well-defined stepwise manner, which includes elements of neutrophil rolling, firm adhesion, and crawling onto the endothelial cell surface before transmigrating across the endothelial barrier. This latter step known as diapedesis can occur at the endothelial cell junction (paracellular) or directly through the endothelial cell body (transcellular). The extravasation cascade is controlled by series of engagement of various adhesive modules, which result in activation of bidirectional signals to neutrophils and endothelial cells for adequate cellular response. This review will focus on recent advances in our understanding of mechanism of leukocyte crawling and diapedesis, with an emphasis on leukocyte-endothelial interactions and the signaling pathways they transduce to determine the mode of diapedesis, junctional or nonjunctional. I will also discuss emerging evidence highlighting key differences in the two modes of diapedesis and why it is clinically important to understand specificity in the regulation of diapedesis.
Rheumatoid Rescue of Misfolded Cellular Proteins by MHC Class II Molecules: A New Hypothesis for Autoimmune Diseases.
Arase H
Adv Immunol · 2016 · PMID 26791856 · Publisher ↗
Misfolded proteins localized in the endoplasmic reticulum are degraded promptly and thus are not transported outside cells. However, misfolded proteins in the endoplasmic reticulum are rescued from protein degradation up...
Misfolded proteins localized in the endoplasmic reticulum are degraded promptly and thus are not transported outside cells. However, misfolded proteins in the endoplasmic reticulum are rescued from protein degradation upon association with major histocompatibility complex (MHC) class II molecules and are transported to the cell surface by MHC class II molecules without being processed to peptides. Studies on the misfolded proteins rescued by MHC class II molecules have revealed that misfolded proteins associated with MHC class II molecules are specific targets for autoantibodies produced in autoimmune diseases. Furthermore, a strong correlation has been observed between autoantibody binding to misfolded proteins associated with MHC class II molecules and the autoimmune disease susceptibility conferred by each MHC class II allele. These new insights into MHC class II molecules suggest that misfolded proteins rescued from protein degradation by MHC class II molecules are recognized as "neo-self" antigens by immune system and are involved in autoimmune diseases as autoantibody targets.
Preface.
Murre C
Adv Immunol · 2015 · PMID 26477372 · Publisher ↗
Abstract loading — click title to view on PubMed.
Long-Range Control of V(D)J Recombination & Allelic Exclusion: Modeling Views.
Outters P, Jaeger S, Zaarour N … +1 more , Ferrier P
Adv Immunol · 2015 · PMID 26477371 · Publisher ↗
Allelic exclusion of immunoglobulin (Ig) and T-cell receptor (TCR) genes ensures the development of B and T lymphocytes operating under the mode of clonal selection. This phenomenon associates asynchronous V(D)J recombin...
Allelic exclusion of immunoglobulin (Ig) and T-cell receptor (TCR) genes ensures the development of B and T lymphocytes operating under the mode of clonal selection. This phenomenon associates asynchronous V(D)J recombination events at Ig or TCR alleles and inhibitory feedback control. Despite years of intense research, however, the mechanisms that sustain asymmetric choice in random Ig/TCR dual allele usage and the production of Ig/TCR monoallelic expressing B and T lymphocytes remain unclear and open for debate. In this chapter, we first recapitulate the biological evidence that almost from the start appeared to link V(D)J recombination and allelic exclusion. We review the theoretical models previously proposed to explain this connection. Finally, we introduce our own mathematical modeling views based on how the developmental dynamics of individual lymphoid cells combine to sustain allelic exclusion.
Chromatin Dynamics and the Development of the TCRα and TCRδ Repertoires.
Carico Z, Krangel MS
Adv Immunol · 2015 · PMID 26477370 · Publisher ↗
The adaptive immune system allows vertebrates to orchestrate highly specific responses to a virtually unlimited milieu of antigens. Effective adaptive immune responses depend on the capacity of T and B lymphocytes to gen...
The adaptive immune system allows vertebrates to orchestrate highly specific responses to a virtually unlimited milieu of antigens. Effective adaptive immune responses depend on the capacity of T and B lymphocytes to generate diverse repertoires of antigen receptors through the recombination of variable (V), diversity (D), and joining (J) gene segments at antigen receptor loci. V(D)J recombination must be carefully regulated during the early stages of T and B lymphocyte development to ensure the proper development of lymphocyte subsets and to maximize antigen receptor combinatorial diversity. Among all T cell receptor (TCR) and immunoglobulin loci, the TCRα/δ (Tcra/Tcrd) locus is unique in its complexity since it undergoes recombination at two distinct stages of T cell development to create distinct TCR proteins that are used by different lineages of T cells. Here, we review the mechanisms that regulate V(D)J recombination at the Tcra/Tcrd locus, with a focus on the dynamic chromatin environment and how it instructs the assembly of the Tcra and Tcrd repertoires. We discuss the dynamics of Tcra and Tcrd repertoire formation in the context of T cell development, and we consider how the recombination program is directed by localized changes in chromatin structure that regulate the accessibility of Tcra and Tcrd gene segments to the V(D)J recombinase. We then move beyond local to address spatial relationships in the nucleus, emphasizing the three-dimensional organization of the Tcra/Tcrd locus as a critical player in understanding long-distance interactions between chromatin regulatory elements as well as long-distance interactions between recombination substrates.
Regulation of Tcrb Gene Assembly by Genetic, Epigenetic, and Topological Mechanisms.
Majumder K, Bassing CH, Oltz EM
Adv Immunol · 2015 · PMID 26477369 · Publisher ↗
The adaptive immune system endows mammals with an ability to recognize nearly any foreign invader through antigen receptors that are expressed on the surface of all lymphocytes. This defense network is generated by V(D)J...
The adaptive immune system endows mammals with an ability to recognize nearly any foreign invader through antigen receptors that are expressed on the surface of all lymphocytes. This defense network is generated by V(D)J recombination, a set of sequentially controlled DNA cleavage and repair events that assemble antigen receptor genes from physically separated variable (V), joining (J), and sometimes diversity (D) gene segments. The recombination process itself must be stringently regulated to minimize oncogenic translocations involving chromosomes that harbor immunoglobulin and T cell receptor loci. Indeed, V(D)J recombination is controlled at several levels, including tissue-, developmental stage-, allele-, and gene segment-specificity. These levels of control are imposed by a collection of architectural and regulatory elements that are distributed throughout each antigen receptor locus. Together, the genetic elements regulate developmental changes in chromatin, transcription, and locus topology that promote or disfavor long-range recombination. This chapter focuses on the cross talk between these mechanisms at the T cell receptor beta (Tcrb) locus, and how they sculpt a diverse TCRβ repertoire while maintaining monospecificity of this antigen receptor on each mature T lymphocyte. We also discuss how insights obtained from studies of Tcrb are more generally relevant to our understanding of gene regulation strategies employed by mammals.
Dynamic Control of Long-Range Genomic Interactions at the Immunoglobulin κ Light-Chain Locus.
Ribeiro de Almeida C, Hendriks RW, Stadhouders R
Adv Immunol · 2015 · PMID 26477368 · Publisher ↗
The Igκ locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells...
The Igκ locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual Vκ segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore involves changes in subnuclear localization, histone modification, DNA demethylation, and three-dimensional locus compaction. In pro-B cells, the Igκ locus adopts a poised conformation as full contraction has been achieved and many key transcription factors already occupy the locus. Subsequently, the combined activation of pre-B cell antigen receptor signaling pathways and attenuation of IL-7R signaling in small resting pre-B cells dramatically modifies the transcription factor landscape, supporting the induction of monoallelic Igκ gene rearrangements. Hereby, the intronic and 3' Igκ enhancer elements coordinately focus their activities in the Vκ region toward frequently used Vκ genes. Recent work has drawn attention to the intriguing role of the CTCF-associated regulatory elements Cer and Sis, which are located in the Vκ-Jκ intervening region and control Igκ locus contraction and Vκ repertoire diversity. This involves CTCF-mediated locus insulation, restricting enhancer activity to the Vκ region and suppressing the preferential recombination to proximal Vκ genes. A picture emerges in which the dynamic control of long-range genomic interactions ensures correct timing of Igκ locus recombination and provides appropriate opportunities for individual Vκ gene segments to engage in Vκ-Jκ rearrangement.
Long-Range Regulation of V(D)J Recombination.
Proudhon C, Hao B, Raviram R … +2 more , Chaumeil J, Skok JA
Adv Immunol · 2015 · PMID 26477367 · Full text
Given their essential role in adaptive immunity, antigen receptor loci have been the focus of analysis for many years and are among a handful of the most well-studied genes in the genome. Their investigation led initiall...
Given their essential role in adaptive immunity, antigen receptor loci have been the focus of analysis for many years and are among a handful of the most well-studied genes in the genome. Their investigation led initially to a detailed knowledge of linear structure and characterization of regulatory elements that confer control of their rearrangement and expression. However, advances in DNA FISH and imaging combined with new molecular approaches that interrogate chromosome conformation have led to a growing appreciation that linear structure is only one aspect of gene regulation and in more recent years, the focus has switched to analyzing the impact of locus conformation and nuclear organization on control of recombination. Despite decades of work and intense effort from numerous labs, we are still left with an incomplete picture of how the assembly of antigen receptor loci is regulated. This chapter summarizes our advances to date and points to areas that need further investigation.
Spatial Regulation of V-(D)J Recombination at Antigen Receptor Loci.
Ebert A, Hill L, Busslinger M
Adv Immunol · 2015 · PMID 26477366 · Publisher ↗
Lymphocytes express a diverse repertoire of antigen receptors, which are able to recognize a large variety of foreign pathogens. Functional antigen receptor genes are assembled by V(D)J recombination in immature B cells...
Lymphocytes express a diverse repertoire of antigen receptors, which are able to recognize a large variety of foreign pathogens. Functional antigen receptor genes are assembled by V(D)J recombination in immature B cells (Igh and Igk) and T cells (Tcr b and Tcra/d). V(D)J recombination takes place in the 3' proximal domain containing the D, J, and C gene segments, whereas 31 (Tcrb) to 200 (Igh) V genes are spread over a large region of 0.67 (Tcrb) to 3 (Igk) megabase pairs. The spatial regulation of V(D)J recombination has been best studied for the Igh locus, which undergoes reversible contraction by long-range looping in pro-B cells. This large-scale contraction brings distantly located VH genes into close proximity of the DJH-rearranged gene segment, which facilitates VH-DJH recombination. The B-cell-specific Pax5, ubiquitous YY1, and architectural CTCF/cohesin proteins regulate Igh locus contraction in pro-B cells by binding to multiple sites in the VH gene cluster. These regulators also control the pro-B-cell-specific activity of the distally located PAIR elements, which may be involved in the regulation of VH-DJH recombination by promoting locus contraction. Moreover, the large VH gene cluster of the Igh locus undergoes flexible long-range looping, which guarantees similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. Importantly, long-range looping is a more general regulatory principle, as other antigen receptor loci also undergo reversible contraction at the developmental stage, where they engage in V-(D)J recombination.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe