Membrane Association of the CD3ε Signaling Domain Is Required for Optimal T Cell Development and Function

The TCR:CD3 complex transduces signals that are critical for optimal T cell development and adaptive immunity. In resting T cells, the CD3 cytoplasmic tail associates with the plasma membrane via a proximal basic-rich stretch (BRS). In this study, we show that mice lacking a functional CD3 epsilon-BRS exhibited substantial reductions in thymic cellularity and limited CD4(-)CD8(-) double-negative (DN) 3 to DN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death and TCR downregulation in all subsequent populations. Furthermore, positive, but not negative, T cell selection was affected in mice lacking a functional CD3 epsilon-BRS, which led to limited peripheral T cell function and substantially reduced responsiveness to influenza infection. Collectively, these results indicate that membrane association of the CD3 signaling domain is required for optimal thymocyte development and peripheral T cell function.