Regulation of cytotoxic T cell and germinal center B cell responses by the c-MYC-AP4 transcription factor cascade

Abstract

Abstract The process of amplifying immune responses by expanding a pool of antigen-specific cells, termed clonal expansion, is an important feature of the adaptive immunity. Whereas clonal expansion of cytotoxic T lymphocytes is required for complete eradication of pathogens in tissues, proliferation of B lymphocytes in the germinal centers is critical for generating a diverse immunoglobulin gene repertoire from which protective antibody carrying multiple mutations can arise. While the proto-oncogene c-MYC is absolutely required for the activation and cell cycle initiation in lymphocytes, its expression is temporally restricted. Activated lymphocytes, however, continue to proliferate after c-MYC levels decay to maximize clonal expansion. It remains unknown how lymphocytes sustain their proliferative program in the absence of c-MYC. We demonstrated that the c-MYC-inducible transcription factor, AP4, is required for sustained expansion of antigen-specific lymphocytes. Mice lacking AP4 in T cells exhibit diminished cytotoxic T cell responses and succumb to West Nile virus infection due to uncontrolled viral replication in the central nervous system. Furthermore, conditional deletion of AP4 in B lymphocytes impaired germinal center growth. These mice failed to control chronic viral infection due to blunted neutralizing antibody responses. ChIP-seq and gene expression analyses revealed a significant overlap between AP4 and c-MYC regulated genes. Thus, the c-MYC-AP4 transcription factor cascade is a general module utilized by activated lymphocytes to maximize immune responses.