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Alternative Splicing and Hypermutation of a Nonproductively Rearranged TCR -Chain in a T Cell Hybridoma¹

Brendan Marshall^2,*, Ruth Schulz, Min Zhou^* and Andrew Mellor^*

^* Institute of Molecular Medicine and Genetics, Program in Molecular Immunology, Medical College of Georgia, Augusta, GA 30912; and Division of Molecular Immunology, National Institute for Medical Research, Mill Hill, London, United Kingdom

Like Ig genes, TCR genes are formed by somatic rearrangements of noncontiguous genomic V, J, and C regions. Unlike Ig genes, somatic hypermutation of TCR V regions is an infrequent event. We describe the occurrence of spontaneous hypermutation in a nonproductively rearranged TCR -chain gene in a clonal T cell hybridoma that had lost its productively rearranged -chain. The mutating hybridoma was eventually supplanted in culture by a nonmutating variant that had restored an open reading frame in the nonproductively rearranged TCR -chain through the use of cryptic splice sites in the V region. Evidence is presented for the presence of cDNA reverse transcripts of the TCR -chain within the hybridoma, suggesting a role for reverse transcriptase in the generation of mutations.

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