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1.
J Immunol ; 198(6): 2244-2248, 2017 03 15.
Article in English | MEDLINE | ID: mdl-28188246

ABSTRACT

IgH class switch recombination (CSR) occurs through the deliberate introduction of activation-induced cytidine deaminase (AID)-instigated DNA double-strand breaks into the IgH loci. Because double-strand breaks are generally highly toxic, mechanisms that regulate AID expression are of much relevance to CSR and genomic integrity; however, effectors of such regulatory processes are still poorly understood. In this article, we show that the transcription factor sex determining region Y-box 2 (Sox2) is expressed in activated B cells, but almost exclusively in those that have undergone CSR. We demonstrate that enforced expression of Sox2 in splenic B cells severely inhibits AID expression and CSR, whereas deletion of Sox2 increases the frequency of IgH:c-Myc translocations. These results suggest that Sox2 may regulate AID expression in class-switched B cells to suppress genomic instability associated with CSR.


Subject(s)
B-Lymphocytes/immunology , Cytidine Deaminase/metabolism , Genes, myc/genetics , SOXB1 Transcription Factors/metabolism , Spleen/immunology , Animals , Cell Differentiation , Cells, Cultured , Cytidine Deaminase/genetics , DNA Breaks, Double-Stranded , Genomic Instability , Immunoglobulin Switch Region , Lymphocyte Activation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , SOXB1 Transcription Factors/genetics , Translocation, Genetic
2.
Eur J Immunol ; 46(3): 523-30, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26799454

ABSTRACT

The mechanism by which the DNA deaminase activation-induced cytidine deaminase (AID) is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is affected. Here, we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a noncoding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of noncoding transcripts during class switching, and has implications in both B cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction.


Subject(s)
Cytidine Deaminase/metabolism , DNA/metabolism , Immunoglobulin Class Switching/genetics , RNA/physiology , Animals , Cytidine Deaminase/genetics , Humans , Immunoglobulin Switch Region/genetics , Immunoglobulins/genetics , Mice , RNA/genetics , Recombination, Genetic
3.
Biomed J ; 37(5): 269-83, 2014.
Article in English | MEDLINE | ID: mdl-25163501

ABSTRACT

Activation-induced Cytidine Deaminase (AID) is an essential regulator of B cell diversification, but its full range of action has until recently been an enigma. Based on homology, it was originally proposed to be an RNA-editing enzyme, but so far, no RNA substrates are known. Rather, it functions by deaminating cytidine, and in this manner, coupled with base-excision repair or mismatch repair machinery, it is a natural mutator. This allows it to play a central role in adaptive immunity, whereby it initiates the processes of class switch recombination and somatic hypermutation to help generate a diverse and high-affinity repertoire of immunoglobulin isotypes. More recently, it has been appreciated that methylated cytidine, already known as a key epigenetic mark on DNA controlling gene expression, can also be a target for AID modification. Coupled with repair machinery, this can facilitate the active removal of methylated DNA. This activity can impact the process of cellular reprogramming, including transition of a somatic cell to pluripotency, which requires major reshuffling of epigenetic memory. Thus, seemingly disparate roles for AID in controlling immune diversity and epigenetic memory have a common mechanistic basis. However, the very activity that is so useful for B cell diversity and cellular reprogramming is dangerous for the integrity of the genome. Thus, AID expression and activity is tightly regulated, and deregulation is associated with diseases including cancer. Here, we review the range of AID functions with a focus on its mechanisms of action and regulation. Major questions remain to be answered concerning how and when AID is targeted to specific loci and how this impacts development and disease.


Subject(s)
Cytidine Deaminase/immunology , DNA Repair/immunology , DNA/immunology , Immunoglobulin Class Switching/immunology , Somatic Hypermutation, Immunoglobulin/immunology , Animals , Humans , RNA/immunology
4.
Adv Immunol ; 122: 1-57, 2014.
Article in English | MEDLINE | ID: mdl-24507154

ABSTRACT

Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cµ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as "Ch genes", e.g., Cγ, Cɛ, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sµ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.


Subject(s)
Cytidine Deaminase/metabolism , DNA Damage/immunology , DNA Repair/immunology , Immunoglobulin Class Switching/genetics , Transcription, Genetic/immunology , V(D)J Recombination/immunology , Animals , B-Lymphocytes/enzymology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , DNA Damage/genetics , DNA Repair/genetics , Humans , Immunoglobulin Class Switching/immunology , Lymphocyte Activation/immunology , Mice , Mice, Transgenic , Recombination, Genetic/genetics , Recombination, Genetic/immunology , Somatic Hypermutation, Immunoglobulin/genetics , Somatic Hypermutation, Immunoglobulin/immunology , T-Lymphocytes/enzymology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , V(D)J Recombination/genetics
5.
Mol Ther ; 19(2): 417-26, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21081905

ABSTRACT

Despite enormous efforts by the scientific community, an effective HIV vaccine remains elusive. To further address to what degree T cells in absence of antibodies may protect against simian immunodeficiency virus (SIV) disease progression, rhesus macaques were vaccinated intramuscularly with a chimpanzee-derived Ad vector (AdC) serotype 6 and then boosted intramuscularly with a serologically distinct AdC vector of serotype 7 both expressing Gag of SIVmac239. Animals were subsequently boosted intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag and Tat of the homologous SIV before mucosal challenge with a high dose of SIVmac239 given rectally. Whereas vaccinated animals showed only a modest reduction of viral loads, their overall survival was improved, in association with a substantial protection from the loss of CD4(+) T cells. In addition, the two vaccinated Mamu-A*01(+) macaques controlled viral loads to levels below detection within weeks after challenge. These data strongly suggest that T cells, while unable to affect SIV acquisition upon high-dose rectal infection, can reduce disease progression. Induction of potent T-cell responses should thus remain a component of our efforts to develop an efficacious vaccine to HIV-1.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Macaca mulatta/immunology , Macaca mulatta/virology , SAIDS Vaccines/immunology , Simian Immunodeficiency Virus/immunology , Simian Immunodeficiency Virus/pathogenicity , Animals , Female , Male
6.
Eur J Immunol ; 40(12): 3426-38, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21108465

ABSTRACT

Most studies on E1-deleted adenovirus (Ad) vectors as vaccine carriers for antigens of HIV-1 have focused on induction of central immune responses, although stimulation of mucosal immunity at the genital tract (GT), the primary port of entry of HIV-1, would also be highly desirable. In this study, different immunization protocols using chimpanzee-derived adenoviral (AdC) vectors expressing Gag of HIV-1 clade B given in heterologous prime-boost regimens were tested for induction of systemic and genital immune responses. Although i.n. immunization stimulated CD8(+) T-cell responses that could be detected in the GT, this route induced only marginal cellular responses in systemic tissues and furthermore numbers of Gag-specific CD8(+) T cells contracted sharply within a few weeks. On the contrary, i.m. immunization induced higher and more sustained frequencies of vaccine-induced cells which could be detected in the GT as well as systemic compartments. Antigen-specific CD8(+) T cells could be detected 1 year after immunization in all compartments analyzed. Genital memory cells secreted IFN-γ, expressed high levels of CD103 and their phenotypes were consistent with a state of activation. Taken together, the results presented here show that i.m. vaccination with chimpanzee-derived (simian) adenovirus vectors is a suitable strategy to induce a long-lived genital CD8(+) T-cell response.


Subject(s)
Adenoviruses, Simian/genetics , CD8-Positive T-Lymphocytes/drug effects , Genitalia/immunology , HIV-1/immunology , gag Gene Products, Human Immunodeficiency Virus/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cells, Cultured , Drug Administration Routes , Female , Genetic Vectors/administration & dosage , Genitalia/drug effects , Genitalia/metabolism , Genitalia/pathology , Immunization , Immunologic Memory/drug effects , Interferon-gamma/metabolism , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Pan troglodytes , gag Gene Products, Human Immunodeficiency Virus/administration & dosage , gag Gene Products, Human Immunodeficiency Virus/genetics , gag Gene Products, Human Immunodeficiency Virus/immunology
7.
J Immunol ; 184(9): 5151-9, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20368274

ABSTRACT

Although previous studies have demonstrated delayed viral clearance and blunted effector T cell responses in aged mice during infection, memory CD8 T cells and especially secondary responses have received less attention. In this study, we show that modest differences in the number of memory CD8 T cells formed in aged versus young animals were associated with altered memory CD8 T cell differentiation. Aged immune mice had increased morbidity and mortality upon secondary viral challenge, suggesting changes in T cell immunity. Indeed, virus-specific memory CD8 T cells from aged mice showed substantially reduced proliferative expansion upon secondary infection using multiple challenge models. In addition, this defect in recall capacity of aged memory CD8 T cells was cell-intrinsic and persisted upon adoptive transfer into young mice. Thus, the poor proliferative potential of memory T cells and altered memory CD8 T cell differentiation could underlie age-related defects in antiviral immunity.


Subject(s)
Aging/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cell Proliferation , Immunologic Memory , Lymphocytic choriomeningitis virus/immunology , Orthomyxoviridae/immunology , Adoptive Transfer , Aging/genetics , Animals , CD8-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/transplantation , Cell Differentiation/immunology , Cell Line , Cytotoxicity Tests, Immunologic , Dogs , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Genetic Predisposition to Disease , Immunodominant Epitopes/genetics , Immunodominant Epitopes/immunology , Immunologic Memory/genetics , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/pathology , Lymphocytic Choriomeningitis/physiopathology , Lymphocytic choriomeningitis virus/genetics , Mice , Mice, Inbred C57BL , Orthomyxoviridae/genetics , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/physiopathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , T-Lymphocyte Subsets/transplantation , T-Lymphocyte Subsets/virology , Vaccinia virus/genetics , Vaccinia virus/immunology
8.
Curr Top Microbiol Immunol ; 333: 291-321, 2009.
Article in English | MEDLINE | ID: mdl-19768412

ABSTRACT

Since their compositions remain uncertain, universal pandemic vaccines are yet to be created. They would aim to protect globally against pandemic influenza viruses that have not yet evolved. Thus they differ from seasonal vaccines to influenza virus, which are updated annually in spring to incorporate the latest circulating viruses, and are then produced and delivered before the peak influenza season starts in late fall and winter. The efficacy of seasonal vaccines is linked to their ability to induce virus-neutralizing antibodies, which provide subtype-specific protection against influenza A viruses. If pandemic vaccines were designed to resemble current vaccines in terms of composition and mode of action, they would have to be developed, tested, and mass-produced after the onset of a pandemic, once the causative virus had been identified. The logistic problems of generating a pandemic vaccine from scratch, conducting preclinical testing, and producing billions of doses within a few months for global distribution are enormous and may well be insurmountable. Alternatively, the scientific community could step up efforts to generate a universal vaccine against influenza A viruses that provides broadly cross-reactive protection through the induction of antibodies or T cells to conserved regions of the virus.


Subject(s)
Disease Outbreaks/prevention & control , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Animals , Attitude , Humans , Immunity, Innate , Influenza A Virus, H1N1 Subtype , Influenza A Virus, H2N2 Subtype , Influenza A Virus, H5N1 Subtype , Influenza, Human/etiology , Influenza, Human/immunology , Risk Factors
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