Regulation of TCRbeta Accessibility and alphabeta T cell development in response to V(D)J recombination mediated signals

The diversity of antigen receptors expressed by the immune system is a function of developmentally regulated site-specific recombination events. A portion of each antigen receptor is encoded by an exon, assembled from V, D, and J segments, during V(D)J recombination. Failure to produce a functional receptor through recombination results death of developing lymphocytes, and can lead to immunodeficiencies. Cells with deficiencies in recombination generally experience developmental impairments at transitions that require signaling through precursor or mature antigen receptors for differentiation. The production of a functional immune system relies upon on the coordination of antigen receptor accessibility, cellular differentiation pathways, and DNA damage response mechanisms during the recombination process. The research presented in this thesis uses various mouse genetic backgrounds to examine the roles of different trans factors and cis elements on TCRbeta locus accessibility, TCRbeta rearrangement, and lymphocyte development to elucidate potential functions in V(D)J recombination. These studies have shown accessibility of the TCRbeta locus is highly dynamic, and likely dependent upon a variety of mechanisms mediating changes in chromatin accessibility in response to developmental cues. The importance of the resolution of DNA breaks is highlighted by deletion of Dicer, a protein critical for miRNA biogenesis; Dicer deletion results in reduced thymocyte survival and developmental impairments in response to recombination-mediated DNA breaks. These analyses indicate that there is a complicated hierarchy of mechanisms in place controlling the steady state level of DNA breaks induced during recombination.