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

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Abstract
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 α-chain gene in a clonal T cell hybridoma that had lost its productively rearranged α-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 α-chain through the use of cryptic splice sites in the Vα region. Evidence is presented for the presence of cDNA reverse transcripts of the TCR α-chain within the hybridoma, suggesting a role for reverse transcriptase in the generation of mutations.