Mechanisms of plasticity in the peripheral T cell receptor repertoire (115.15)

Abstract

Abstract We recently reported a method for amplifying paired T cell receptor (TCR) αβ CDR3 regions from single cells in mice and have developed a similar protocol for human cells. Using this technique, we have discovered a surprising plasticity in peripheral TCR repertoire, particularly under conditions of inflammation. This plasticity includes two major mechanisms: TCR modulation and TCR revision. Modulation consists of the up or down regulation of secondary allele expression, almost exclusively from the TCRα locus. Revision results in changes to the amino acid sequence of the TCR by de novo rearrangement. Here we describe the upregulation of both processes in CD8+ T cells derived from influenza-infected lungs when compared to circulating naïve T cells. In particular, instances of modulation and dual chain expression are elevated over the course of a primary influenza T cell response, whereas in recall responses memory cells express only a single allele of each TCR chain. In repeated infections, revised TCRs are observed by using out of frame TCR sequences as an internal, lineage specific, barcode. The relative contribution of each mechanism to the activation of autoreactive T cells is assessed in genetic models.