Analysis of a T cell receptor gene as a target of the somatic hypermutation mechanism.

In an effort to identify cis-acting elements required for targeting of the somatic hypermutation process in mice, we examined whether a T cell receptor (TCR) transgene under the control of the immunoglobulin (Ig) heavy (H) chain intron enhancer would be mutated in antigen-stimulated B cells. Hybridomas were established from splenic B cells of mice carrying two copies of the TCR transgene after hyperimmunization with phosphorylcholine keyhole limpet hemocyanin. Northern analysis revealed that all of the transgene-containing hybridomas expressed the TCR mRNA. Multiple somatic point mutations were found in seven of eight endogenous Ig VH genes examined. In contrast, 29 of 32 TCR genes examined contained no mutations. One potential mutation was seen in each of the three other TCR genes. Our data indicate that although the TCR transgene is expressed in B cells, it is not efficiently targeted by the mutator mechanism. Furthermore, the presence of an Ig H chain enhancer is itself not sufficient for targeting of the somatic hypermutation mechanism.

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Constitutive Expression of AID Leads to Tumorigenesis

Journal of Experimental Medicine ◽

10.1084/jem.20030275 ◽

2003 ◽

Vol 197 (9) ◽

pp. 1173-1181 ◽

Cited By ~ 323

Author(s):

Il-mi Okazaki ◽

Hiroshi Hiai ◽

Naoki Kakazu ◽

Shuichi Yamada ◽

Masamichi Muramatsu ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Genome Stability ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Point Mutations ◽

Constitutive Expression ◽

Cell Receptor ◽

Genetic Alterations ◽

Artificial Substrates

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.

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TRIP - T cell receptor/immunoglobulin profiler

BMC Bioinformatics ◽

10.1186/s12859-020-03669-1 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Maria Th. Kotouza ◽

◽

Katerina Gemenetzi ◽

Chrysi Galigalidou ◽

Elisavet Vlachonikola ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Web Application ◽

Somatic Hypermutation ◽

Sequence Data ◽

Receptor Gene ◽

Antigen Receptor ◽

Cell Receptor ◽

Nucleotide Composition ◽

Depth Analysis

Abstract Background Antigen receptors are characterized by an extreme diversity of specificities, which poses major computational and analytical challenges, particularly in the era of high-throughput immunoprofiling by next generation sequencing (NGS). The T cell Receptor/Immunoglobulin Profiler (TRIP) tool offers the opportunity for an in-depth analysis based on the processing of the output files of the IMGT/HighV-Quest tool, a standard in NGS immunoprofiling, through a number of interoperable modules. These provide detailed information about antigen receptor gene rearrangements, including variable (V), diversity (D) and joining (J) gene usage, CDR3 amino acid and nucleotide composition and clonality of both T cell receptors (TR) and B cell receptor immunoglobulins (BcR IG), and characteristics of the somatic hypermutation within the BcR IG genes. TRIP is a web application implemented in R shiny. Results Two sets of experiments have been performed in order to evaluate the efficiency and performance of the TRIP tool. The first used a number of synthetic datasets, ranging from 250k to 1M sequences, and established the linear response time of the tool (about 6 h for 1M sequences processed through the entire BcR IG data pipeline). The reproducibility of the tool was tested comparing the results produced by the main TRIP workflow with the results from a previous pipeline used on the Galaxy platform. As expected, no significant differences were noted between the two tools; although the preselection process seems to be stricter within the TRIP pipeline, about 0.1% more rearrangements were filtered out, with no impact on the final results. Conclusions TRIP is a software framework that provides analytical services on antigen receptor gene sequence data. It is accurate and contains functions for data wrangling, cleaning, analysis and visualization, enabling the user to build a pipeline tailored to their needs. TRIP is publicly available at https://bio.tools/TRIP_-_T-cell_Receptor_Immunoglobulin_Profiler.

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Pathogenesis of B cell lymphoma in a patient with AIDS

Blood ◽

10.1182/blood.v67.3.612.612 ◽

1986 ◽

Vol 67 (3) ◽

pp. 612-615 ◽

Cited By ~ 100

Author(s):

JE Groopman ◽

JL Sullivan ◽

C Mulder ◽

D Ginsburg ◽

SH Orkin ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Receptor ◽

Dna Sequences ◽

Receptor Gene ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Molecular Techniques ◽

Barr Virus

Abstract Lymphoma occurs at increased frequency in patients with the acquired immunodeficiency syndrome (AIDS). We studied, using serologic and molecular techniques, one such lymphoma for (a) evidence of infection with human T lymphotropic virus, type III (HTLV-III), and Epstein-Barr virus (EBV), (b) monoclonal rearrangement of immunoglobulin and T cell receptor genes, and (c) rearrangement of the c-myc oncogene. Immunoglobulin and T cell receptor gene studies demonstrated that the tumor was of monoclonal B cell origin. Similar to cases of Burkitt's lymphoma unrelated to AIDS, there were DNA sequences in the lymphoma that hybridized to EBV-specific probes and demonstrated evidence of c- myc rearrangement. HTLV-III sequences were not detected in the malignant B cells. The pathogenesis of some B cell neoplasms in patients with the syndrome may involve transformation by EBV and deregulation of oncogene expression without direct infection of the malignant B cells by HTLV-III.

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Pathogenesis of B cell lymphoma in a patient with AIDS

Blood ◽

10.1182/blood.v67.3.612.bloodjournal673612 ◽

1986 ◽

Vol 67 (3) ◽

pp. 612-615

Author(s):

JE Groopman ◽

JL Sullivan ◽

C Mulder ◽

D Ginsburg ◽

SH Orkin ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Receptor ◽

Dna Sequences ◽

Receptor Gene ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Molecular Techniques ◽

Barr Virus

Lymphoma occurs at increased frequency in patients with the acquired immunodeficiency syndrome (AIDS). We studied, using serologic and molecular techniques, one such lymphoma for (a) evidence of infection with human T lymphotropic virus, type III (HTLV-III), and Epstein-Barr virus (EBV), (b) monoclonal rearrangement of immunoglobulin and T cell receptor genes, and (c) rearrangement of the c-myc oncogene. Immunoglobulin and T cell receptor gene studies demonstrated that the tumor was of monoclonal B cell origin. Similar to cases of Burkitt's lymphoma unrelated to AIDS, there were DNA sequences in the lymphoma that hybridized to EBV-specific probes and demonstrated evidence of c- myc rearrangement. HTLV-III sequences were not detected in the malignant B cells. The pathogenesis of some B cell neoplasms in patients with the syndrome may involve transformation by EBV and deregulation of oncogene expression without direct infection of the malignant B cells by HTLV-III.

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