Hyperresponse to T-Cell Receptor Signaling and Apoptosis of Id1 Transgenic Thymocytes

Abstract

The basic helix-loop-helix transcription factors, E2A and HEB, play important roles in T-cell development at multiple checkpoints. Expression of their inhibitor, Id1, abolishes the function of both transcription factors in a dose-dependent manner. The Id1 transgenic thymus is characterized by an accumulation of CD4⁻ CD8⁻ CD44⁺ CD25⁻ thymocytes, a dramatic reduction of CD4⁺ CD8⁺ thymocytes, and an abundance of apoptotic cells. Here we show that these apoptotic cells carry functional T-cell receptors (TCRs), suggesting that apoptosis occurs during T-cell maturation. In contrast, viable Id1 transgenic CD4 single positive T cells exhibit costimulation-independent proliferation upon treatment with anti-CD3 antibody, probably due to a hyperresponse to TCR signaling. Furthermore, Id1 expression causes apoptosis of CD4 and CD8 double- or single-positive thymocytes in HY- or AND-TCR transgenic mice under conditions that normally support positive selection. Collectively, these results suggest that E2A and HEB proteins are crucial for controlling the threshold for TCR signaling, and Id1 expression lowers the threshold, resulting in apoptosis of developing thymocytes.

We thank Dongsoo Kim for preparation of the genomic DNA from Id1 transgenic mice used in this study and Viji Dandapani for excellent assistance in cell sorting. We thank Yuanzheng Yang, Ying Zhao, and Mei-Ying Xiong for technical assistance. We are grateful to Linda Thompson and Darryll Dudley for critical reading of the manuscript.

The study was supported by grants from the National Institutes of Health to X.-H.S. (AI33597, CA77553, and RR15577 [COBRE award]).