RESUMEN
Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.
Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/química , Infección por el Virus Zika/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Brasil , Femenino , Humanos , Memoria Inmunológica , Leucocitos Mononucleares/inmunología , Masculino , México , Ratones , Infección por el Virus Zika/sangreRESUMEN
Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
Asunto(s)
Anticuerpos Neutralizantes/administración & dosificación , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/administración & dosificación , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Ácidos Hidroxámicos/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/inmunología , Ratones , Receptores Fc/inmunología , VorinostatRESUMEN
Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Especificidad de Anticuerpos/inmunología , Modelos Animales de Enfermedad , Infecciones por VIH/virología , VIH-1/genética , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , VIH-1/aislamiento & purificación , Semivida , Humanos , Inmunización Pasiva , Ratones , Ratones Endogámicos NOD , Factores de Tiempo , Carga Viral/efectos de los fármacosRESUMEN
MicroRNAs (miRNAs) are small noncoding RNAs that regulate vast networks of genes that share miRNA target sequences. To examine the physiologic effects of an individual miRNA-mRNA interaction in vivo, we generated mice that carry a mutation in the putative microRNA-155 (miR-155) binding site in the 3'-untranslated region of activation-induced cytidine deaminase (AID), designated Aicda(155) mice. AID is required for immunoglobulin gene diversification in B lymphocytes, but it also promotes chromosomal translocations. Aicda(155) caused an increase in steady-state Aicda mRNA and protein amounts by increasing the half-life of the mRNA, resulting in a high degree of Myc-Igh translocations. A similar but more pronounced translocation phenotype was also found in miR-155-deficient mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID.
Asunto(s)
Linfocitos B/enzimología , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Genes myc , Cadenas Pesadas de Inmunoglobulina/genética , MicroARNs/metabolismo , Translocación Genética , Regiones no Traducidas 3' , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Genes de Inmunoglobulinas , Cambio de Clase de Inmunoglobulina , Lipopolisacáridos/inmunología , Ratones , Ratones Mutantes , MicroARNs/genética , Mutación , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Hipermutación Somática de InmunoglobulinaRESUMEN
Cancer-initiating translocations such as those associated with lymphomas require the formation of paired DNA double-strand breaks (DSBs). Activation-induced cytidine deaminase (AID) produces widespread somatic mutation in mature B cells; however, the extent of "off-target" DSB formation and its role in translocation-associated malignancy is unknown. Here, we show that deregulated expression of AID causes widespread genome instability, which alone is insufficient to induce B cell lymphoma; transformation requires concomitant loss of the tumor suppressor p53. Mature B cell lymphomas arising as a result of deregulated AID expression are phenotypically diverse and harbor clonal reciprocal translocations involving a group of Immunoglobulin (Ig) and non-Ig genes that are direct targets of AID. This group includes miR-142, a previously unknown micro-RNA target that is translocated in human B cell malignancy. We conclude that AID produces DSBs throughout the genome, which can lead to lymphoma-associated chromosome translocations in mature B cells.
Asunto(s)
Cromosomas de los Mamíferos/genética , Citidina Desaminasa/metabolismo , Roturas del ADN de Doble Cadena , Genes de Inmunoglobulinas/genética , Linfoma de Células B/enzimología , Linfoma de Células B/genética , Translocación Genética , Animales , Linfocitos B/citología , Linfocitos B/enzimología , Diferenciación Celular/genética , Células Cultivadas , Inestabilidad Cromosómica/genética , Daño del ADN , Humanos , Cambio de Clase de Inmunoglobulina/genética , Cariotipificación , Linfoma de Células B/patología , Ratones , Ratones Transgénicos , MicroARNs/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-myc/genética , Hipermutación Somática de Inmunoglobulina/genética , Proteína p53 Supresora de Tumor/deficienciaRESUMEN
Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.
Asunto(s)
Antirretrovirales/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/prevención & control , VIH-1/efectos de los fármacos , VIH-1/inmunología , Inmunoterapia/métodos , Animales , Antirretrovirales/farmacología , Anticuerpos Neutralizantes/farmacología , Cartilla de ADN/genética , ADN Viral/metabolismo , Dependovirus , Quimioterapia Combinada , Humanos , Ratones , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Carga Viral/efectos de los fármacosRESUMEN
To explore the influence of genetics on homeostatic regulation of dendritic cell (DC) numbers, we present a screen of DCs and their progenitors in lymphoid and non-lymphoid tissues in Collaborative Cross (CC) and Diversity Outbred (DO) mice. We report 30 and 71 loci with logarithm of the odds (LOD) scores >8.18 and ranging from 6.67 to 8.19, respectively. The analysis reveals the highly polygenic and pleiotropic architecture of this complex trait, including many of the previously identified genetic regulators of DC development and maturation. Two SNPs in genes potentially underlying variation in DC homeostasis, a splice variant in Gramd4 (rs235532740) and a missense variant in Orai3 (rs216659754), are confirmed by gene editing using CRISPR-Cas9. Gramd4 is a central regulator of DC homeostasis that impacts the entire DC lineage, and Orai3 regulates cDC2 numbers in tissues. Overall, the data reveal a large number of candidate genes regulating DC homeostasis in vivo.
Asunto(s)
Células Dendríticas , Sitios de Carácter Cuantitativo , Animales , Células Dendríticas/metabolismo , Ratones , Sitios de Carácter Cuantitativo/genética , Polimorfismo de Nucleótido Simple , Ratones Endogámicos C57BL , Recuento de Células , Mapeo Cromosómico , HomeostasisRESUMEN
Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-J(H) region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre-B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-J(H) translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID(-/-) IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.
Asunto(s)
Cromosomas de los Mamíferos/genética , Citidina Desaminasa/metabolismo , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética , Animales , Rotura Cromosómica , Citidina Desaminasa/deficiencia , Femenino , Humanos , Interleucina-6/deficiencia , Masculino , Ratones , Ratones Transgénicos , Hipermutación Somática de Inmunoglobulina/genéticaRESUMEN
Chromosome translocations between Ig (Ig) and non-Ig genes are frequently associated with B-cell lymphomas in humans and mice. The best characterized of these is c-myc/IgH translocation, which is associated with Burkitt's lymphoma. These translocations are caused by activation-induced cytidine deaminase (AID), which produces double-strand DNA breaks in both genes. c-myc/IgH translocations are rare events, in part because ATM, p53, and p19 actively suppress them. To further define the mechanism of protection against the accumulation of cells that bear c-myc/IgH translocation, we assayed B cells from mice that carry mutations in cell-cycle and apoptosis regulator proteins that act downstream of p53. We find that PUMA, Bim, and PKCdelta are required for protection against c-myc/IgH translocation, whereas Bcl-XL and BAFF enhance c-myc/IgH translocation. Whether these effects are general or specific to c-myc/IgH translocation and whether AID produces dsDNA breaks in genes other than c-myc and Ig is not known. To examine these questions, we developed an assay for translocation between IgH and Igbeta, both of which are somatically mutated by AID. Igbeta/IgH, like c-myc/IgH translocations, are AID-dependent, and AID is responsible for lesions on IgH and the non-IgH translocation partners. However, ATM, p53, and p19 do not protect against Igbeta/IgH translocations. Instead, B cells are protected against Igbeta/IgH translocations by a BAFF- and PKCdelta-dependent pathway. We conclude that AID-induced double-strand breaks in non-Ig genes other than c-myc lead to their translocation, and that at least two nonoverlapping pathways protect against translocations in primary B cells.
Asunto(s)
Citidina Desaminasa/metabolismo , Translocación Genética , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada , Linfocitos B/inmunología , Proteína 11 Similar a Bcl2 , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica , Células Cultivadas , Inhibidor p19 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p19 de las Quinasas Dependientes de la Ciclina/metabolismo , Citidina Desaminasa/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genes de Inmunoglobulinas , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteína Quinasa C-delta/genética , Proteína Quinasa C-delta/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Hipermutación Somática de Inmunoglobulina , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies. However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks. The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX, p53 binding protein 1 (53BP1) or the non-homologous end-joining protein Ku80. In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc-Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.
Asunto(s)
Citidina Desaminasa/metabolismo , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Genes myc/genética , Inestabilidad Genómica/genética , Modelos Genéticos , Translocación Genética/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Linfocitos B/metabolismo , Línea Celular , Citidina Desaminasa/genética , Daño del ADN/genética , Expresión Génica , Cambio de Clase de Inmunoglobulina/genética , Ratones , Mutación/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Mutación/genética , Virus Zika/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/química , Anticuerpos Neutralizantes/inmunología , Virus del Dengue/inmunología , Epítopos/inmunología , Células HEK293 , Humanos , Macaca , Ratones Noqueados , Dominios ProteicosRESUMEN
Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian-human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Inmunoterapia/métodos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Neutralizantes/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Células HEK293 , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Macaca mulatta , Ratones Endogámicos NOD , Ratones Noqueados , Mutación/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Proteínas del Envoltorio Viral/inmunología , Carga Viral/inmunologíaRESUMEN
CD4(+)CD25(+)Foxp3(+) natural regulatory T cells (T reg cells) maintain self-tolerance and suppress autoimmune diseases such as type 1 diabetes and inflammatory bowel disease (IBD). In addition to their effects on T cells, T reg cells are essential for maintaining normal numbers of dendritic cells (DCs): when T reg cells are depleted, there is a compensatory Flt3-dependent increase in DCs. However, little is known about how T reg cell homeostasis is maintained in vivo. We demonstrate the existence of a feedback regulatory loop between DCs and T reg cells. We find that loss of DCs leads to a loss of T reg cells, and that the remaining T reg cells exhibit decreased Foxp3 expression. The DC-dependent loss in T reg cells leads to an increase in the number of T cells producing inflammatory cytokines, such as interferon gamma and interleukin 17. Conversely, increasing the number of DCs leads to increased T reg cell division and accumulation by a mechanism that requires major histocompatibility complex II expression on DCs. The increase in T reg cells induced by DC expansion is sufficient to prevent type 1 autoimmune diabetes and IBD, which suggests that interference with this feedback loop will create new opportunities for immune-based therapies.
Asunto(s)
Células Dendríticas/fisiología , Diabetes Mellitus Tipo 1/inmunología , Retroalimentación/fisiología , Homeostasis/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Linfocitos T Reguladores/fisiología , Animales , Anticuerpos Monoclonales , Proliferación Celular , Citocinas/metabolismo , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Genes MHC Clase II/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Análisis de Regresión , Linfocitos T Reguladores/metabolismoRESUMEN
In the steady state, dendritic cells (DCs) in the lymph node induce T cell tolerance to self antigens. Innate signals trigger the maturation of tissue DCs, which migrate into lymph nodes and activate T cells. To examine DCs in vivo, we produced transgenic mice whose DCs expressed enhanced yellow fluorescent protein. Two-photon microscopy of lymph nodes in live mice showed that most of the steady-state DCs were enmeshed in an extensive network and remained in place while actively probing adjacent T cells with their processes. Mature DCs were more motile than steady-state DCs and were rapidly dispersed and integrated into the sessile network, facilitating their interaction with migrating T cells.
Asunto(s)
Comunicación Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Diferenciación Celular , Movimiento Celular , Células Dendríticas/metabolismo , Ganglios Linfáticos/citología , Ratones , Ratones Transgénicos , Microscopía Confocal , Microscopía Fluorescente , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
We have identified a silencer and an antisilencing element that interact at a distance of 85 kilobases to regulate expression of the recombination activating genes Rag1 and Rag2 in thymocytes. Transgenic experiments showed that Rag promoter-proximal cis elements directed tissue-specific expression and that a Runx-dependent intergenic silencer suppressed expression in developing T cells. Deletion of the antisilencing element from the genomic Rag locus unmasked the intergenic silencer and abrogated Rag expression in developing CD4(+)CD8(+) T cells. We speculate that the Rag antisilencing element belongs to a class of cis elements that might be useful for genome diversification by activating genes encoded by otherwise silent transposable elements.
Asunto(s)
Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Genes RAG-1 , Elementos Silenciadores Transcripcionales , Timo/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Ratones , Proteínas Proto-Oncogénicas/metabolismo , Eliminación de Secuencia , Factores de Transcripción/metabolismoRESUMEN
Chromosome translocations between c-myc and immunoglobulin (Ig) are associated with Burkitt's lymphoma in humans and with pristane- and IL6-induced plasmacytomas in mice. These translocations frequently involve Ig switch regions, suggesting that they might be the result of aberrant Ig class switch recombination (CSR). However, a direct link between CSR and chromosome translocations has not been established. We have examined c-myc/IgH translocations in IL6 transgenic mice that are mutant for activation induced cytidine deaminase (AID), the enzyme that initiates CSR. Here we report that AID is essential for the c-myc/IgH chromosome translocations induced by IL6.