Date of Award
Doctor of Philosophy (PhD)
The process of amplifying immune responses by expanding a small number 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 intracellular pathogens, proliferation of B lymphocytes in the germinal centers (GC) 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 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 CD8 T cells exhibit diminished T cell clonal expansion and succumb to West Nile virus infection due to uncontrolled viral replication in the central nervous system. Genetic ablation of AP4 in B lymphocytes impaired GC growth. These mice failed to control persistent viral infection due to blunted neutralizing antibody development. The accumulation of AP4 requires IL-2 and IL-21 signals in CD8 T cells and GC B cells, respectively, suggesting that AP4 functions as a gauge for extracellular microenvironment and scales the magnitude of lymphocyte expansion accordingly. Mechanistically, ChIP-seq and gene expression analyses suggest that AP4 compensates for early termination of c-MYC by maintaining the transcription of activation signature genes initiated by c-MYC. Thus, both CD8 T and GC B cells have evolved to utilize the c-MYC-AP4 transcription factor cascade to maximize immune responses.
Chair and Committee
Kenneth M. Murphy, Emil R. Unanue, Eugene M. Oltz, Chyi-song Hsieh, Deepta Bhattacharya
Chou, Chun, "Regulation of durable adaptive immune response by the c-MYC-AP4 transcriptional cascade" (2016). Arts & Sciences Electronic Theses and Dissertations. 837.