ORCID

https://orcid.org/0000-0001-7147-4236

Date of Award

Summer 8-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

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.

Language

English (en)

Chair and Committee

Takeshi Egawa

Committee Members

Kenneth M. Murphy, Emil R. Unanue, Eugene M. Oltz, Chyi-song Hsieh, Deepta Bhattacharya

Comments

Permanent URL: https://doi.org/doi:10.7936/K7R20ZR6

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