T cell receptor repertoire features display universal rules for selection and plasticity in the functional CD4 T cell subsets

Abstract

Helper T cell choice of functional subset may depend on the mode and strength of T cell receptor interaction with peptide-MHC complex on antigen presenting cells. However, the extent, complexity, and homogeneity of this influence of TCR structure on the selection into a functional subset, as well as further stability of acquired clonal programs remain poorly studied. Here we present the first analysis of deep sequenced T-cell receptor repertoires of the eight effector CD4 T cell subsets (Th1, Th2, Th2a, Th17, Th1-17, Th22, Treg, and Tfh) from peripheral blood of 5 healthy donors, revealing unexpectedly prominent, multivariate subset-specific differences that are highly reproducible across unrelated donors. Similar analysis performed for the sorted naive CD4 T cell subsets showed that specific TCR features of Tregs (short and strongly interacting CDR3 region) are rooted in thymic selection, while differences between other subsets accumulate later upon T cell functional engagement. We next provide the first deep analysis of the plasticity of human effector CD4 subsets ex vivo. We demonstrate high plasticity within Th17 and Th22 functional subsets and prominent clonal exchange of both Th17 and Th22 with Th2. Th1-17 subset shares clones with Th1 but not with the Th17 subset. Finally, we investigate relative publicity of effector CD4 subset repertoires across donors. We reveal high publicity of Treg and Tfh, and high privacy of Th22 and Th2a repertoires, which corresponds to the number of added N-nucleotides for these subsets, suggesting their earlier fetal and evolutionary origin. Altogether, we provide the first detailed picture of distinct repertoire features, plasticity, and publicity of helper CD4 T cell subsets.