The Role of T cell Receptor Avidity in Determining T-helper Differentiation Fate of Human CD4+ T cells

Abstract

The role of the T cell receptor (TCR) in antigen recognition and activation of T lymphocytes is well established. However, how the TCR affects T-helper differentiation/skewing is less well understood, particularly for human CD4 ⁺ (CD4) T cell subsets. Here we investigate the role of TCR specific antigen avidity in differentiation and maintenance of human Th1, Th2 and Th17 subsets. Two human TCRs, both specific for the same peptide antigen but with different avidities, were cloned and expressed in human CD4 T cells. These TCR engineered cells were then stimulated with different concentrations of specific antigen under non T-helper differentiated, pre-differentiated, and differentiating conditions. We show that TCR avidity can control the percentage of IL-4 and IFN-γ co-expression in non-differentiated TCR engineered cells. Further, we show that effector function can be maintained in a TCR avidity-dependent manner in pre-differentiated TCR engineered cells. Lastly, we show that increased TCR avidity can accelerate Th1 and inhibit Th2 differentiation of TCR engineered cells. This study advances the knowledge of regulating and predicting the differentiation of human CD4 T-helper cells.