T cells can induce somatic mutation in B cell receptor-engaged BL2 Burkitt's lymphoma cells independently of CD40-CD40 ligand interactions.
The B cell surface trigger(s) and the molecular mechanism(s) of somatic hypermutation remain unknown, partly because of the lack of amendable in vitro models. Recently, however, we reported that upon B cell receptor cross-linking and coculture with activated T cells, the Burkitt's lymphoma cell line BL2 introduces mutations in its IgVH gene in vitro. We now confirm the relevance of our culture model by establishing that the entire spectrum of somatic mutations observed in vivo, including insertions and deletions, could be found in the DNA of BL2 cells. Additionally, we show that among four human B cell lines, only two with a centroblast-like phenotype can be induced to mutate. Triggering of somatic mutations in BL2 cells requires intimate T-B cell contacts and is independent of CD40-CD40-ligand (CD40L) interactions as shown by 1) the lack of effect of anti-CD40 and/or anti-CD40L blocking Abs on somatic mutation and 2) the ability of a CD40L-deficient T cell clone (isolated from an X-linked hyper-IgM syndrome patient) to induce somatic mutation in B cell receptor-engaged BL2 cells. Thus, our in vitro model reveals that T-B cell membrane interactions through surface molecules different from CD40-CD40L can trigger somatic hypermutation.
Denépoux
S
S
Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
Fournier
N
N
Péronne
C
C
Banchereau
J
J
Lebecque
S
S
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001482:Base Composition; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002450:Cell Communication / Q000276:immunology; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008024:Ligands; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand