Membrane association of the CD3ε signaling domain is required for optimal T cell development and function

• Published in: The Journal of immunology (1950) 2014-07, Vol.193 (1), p.258-267
• Main Authors: Bettini, Matthew L, Guy, Clifford, Dash, Pradyot, Vignali, Kate M, Hamm, David E, Dobbins, Jessica, Gagnon, Etienne, Thomas, Paul G, Wucherpfennig, Kai W, Vignali, Dario A A
• Format: Article
• Language: English
• Subjects: Animals; CD3 Complex - genetics; CD3 Complex - immunology; Cell Membrane - genetics; Cell Membrane - immunology; Mice; Mice, Knockout; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Signal Transduction - genetics; Signal Transduction - immunology; Thymocytes - cytology; Thymocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400322

The TCR:CD3 complex transduces signals that are critical for optimal T cell development and adaptive immunity. In resting T cells, the CD3ε cytoplasmic tail associates with the plasma membrane via a proximal basic-rich stretch (BRS). In this study, we show that mice lacking a functional CD3ε-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 CD3ε-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 CD3ε signaling domain is required for optimal thymocyte development and peripheral T cell function.