Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

Abstract

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

Immune Equilibrium Depends on the Interaction Between Recognition and Presentation Landscapes

“…TCRs of Treg cells exert relatively higher affinity to self-antigens, bind cognate pMHC ligands less specifically and have lower averaged energy of TCR-pMHC binding than Tfh cells that bind cognate pMHC ligands with high affinity and have a higher energy of TCR-pMHC binding, which agrees with previous data (52)(53)(54). At the same time, such differences were also observed in other subpopulations: amino acidic characteristics of the CDR3 loop among the populations Th1/Th1-17/Th17 were similar to the characteristics of Tfh, while among populations Th22/Th2a/Th2, there was a similarity with Treg cells (48). Besides, different subpopulations of T cells were distinguished by a diversity of TCR repertoires.…”

“…The study of these parameters revealed the differences in the physicochemical properties of the CDR3 TCR loop at the level of different subpopulations of T cells. It was shown that Treg cells have TCRs with high cross-reactivity, while follicular helpers Tfh have TCRs with minimal cross-reactivity (48). TCRs of Treg cells exert relatively higher affinity to self-antigens, bind cognate pMHC ligands less specifically and have lower averaged energy of TCR-pMHC binding than Tfh cells that bind cognate pMHC ligands with high affinity and have a higher energy of TCR-pMHC binding, which agrees with previous data (52)(53)(54).…”

“…Transdifferentiation between the different T-cell subpopulations is well-known. However, not long ago, it was established that functionally different subpopulations of CD4 + cells expressed TCRs with different physicochemical properties and had different profiles of VDJ recombination, which affected their tendency to differentiate into each other (48). In their study, Kasatskaya et al (48) focused on some characteristics of the CDR3 region in different subpopulations of T cells.…”

“…However, not long ago, it was established that functionally different subpopulations of CD4 + cells expressed TCRs with different physicochemical properties and had different profiles of VDJ recombination, which affected their tendency to differentiate into each other (48). In their study, Kasatskaya et al (48) focused on some characteristics of the CDR3 region in different subpopulations of T cells. The authors of that study evaluated different properties of amino acids in the CDR3 loop, the hydrophobicity of the loop (Kidera factor 4) (49), the length of the CDR3 loop, the predicted averaged binding energy of the TCR-pMHC (50,51), and some other parameters that generally influence the affinity of Ag-specific TCR-pMHC interaction and the degree of TCR cross-reactivity (48).…”

“…In their study, Kasatskaya et al (48) focused on some characteristics of the CDR3 region in different subpopulations of T cells. The authors of that study evaluated different properties of amino acids in the CDR3 loop, the hydrophobicity of the loop (Kidera factor 4) (49), the length of the CDR3 loop, the predicted averaged binding energy of the TCR-pMHC (50,51), and some other parameters that generally influence the affinity of Ag-specific TCR-pMHC interaction and the degree of TCR cross-reactivity (48). The study of these parameters revealed the differences in the physicochemical properties of the CDR3 TCR loop at the level of different subpopulations of T cells.…”