The Abundance of α-Chain-Centric TCRs in the Mouse Repertoire of Primarily Activated Effectors and Reactivated Memory...

Chain centricity is a feature of some T cell receptors (TCRs), in which one hemi-chain (α or β) dominates in antigen recognition. The exact proportion of chain-centric TCRs in the native repertoire is currently unknown, as is their inclusion in the repertoires of different functional T cell subsets. Discovering these main issues will elucidate the origin of chain-centric clonotypes and greatly improve their detection in bulk repertoires. In this work, the frequency and abundance of clonotypes with the dominant-active α-chain TCR (TCRα), i.e., α-chain-centric clonotypes, were identified in the mouse repertoires of primarily activated effectors and reactivated memory cells specific to tumor alloantigens. Screening tests in vitro showed that α-chain-centric clonotypes were contained in both repertoires, indicating that α-chain centricity could be an inherent feature of some TCRs. In both repertoires, the proportions of such clonotypes were found to be 20% to 25% of clonotypes expanded during antigenic stimulation. Transduction of naïve T cells with the individual dominant-active TCRα from both repertoires generated cytotoxic effectors that specifically killed the cognate tumor cells in vitro. This study confirmed previous findings that T cell modification with TCRα of α-chain-centric clonotypes generated functionally active antigen-specific effectors. Clonotypes with the dominant-active TCRα were actively involved in the primary allogeneic response. In contrast to primarily activated effectors, α-chain-centric memory clonotypes had the complementarity-determining region 3 (CDR3) with the unique physicochemical signature of shorter length, increased charge, and lower volume and polarity. Here, α-chain-centric memory clonotypes were proposed as promising candidates for adoptive TCR-T cell therapy.