The mammalian lymphoid system offers an excellent model to study the interplay between tissue specific and ubiquitous developmental pathways. The most important lymphoid specific component is the antigen specific receptor. These receptors are encoded by discrete gene segments that undergo a developmentally regulated gene rearrangement, VDJ recombination, to generate a diverse antigen receptor repertoire. For several years we have been studying the regulation of this process and currently, with the in vitro recapitulation of VDJ recombination, we began to explore the detailed molecular mechanism of the recombination process. In addition, we have entered collaborations to study the DNA repair pathways that participate in restoring genome integrity following recombination-induced DNA damage. These studies involve the use of genetically mutant animals to assess the role of different DNA repair mechanisms in VDJ recombination.
Immunoglobulin genes undergo further somatic changes during the antigen induced B-lymphocyte response. These changes, class switch recombination and somatic hypermutation, are initiated by a common mutation event introduced by a recently discovered enzyme, activation-induced cytidine deaminase (AICDA). Expression of AICDA is restricted to a narrow window of B-cell maturation, which may be a critical to restrict the otherwise hazardous mutagenic activities of AICDA. With a combination of molecular and transgenic techniques we are trying to define the transcriptional control of AICDA gene expression in order to better understand the molecular regulation of antigen-specific B-cell responses.
Studies of the rearrangement and expression of the T-cell receptor (TCR) genes have lead us to realize that the TCR is critical to final maturation of T lymphocytes but not to the earliest steps of T-cell differentiation. We began a comprehensive analysis of gene expression patterns during early thymocyte differentiation with particular emphasis on the expression of various classes of transcription factors. We are exploring the role of these factors in hemato- and lymphopoetic differentiation by introducing them into tissue culture cell lines and living animals by transgenic technology and by analyzing tissue-specific knock-out models. Our ultimate goal is to integrate the function of the lymphoid specific and ubiquitous external signals as well as the cell-autonomous transcriptional program into a coherent framework of lymphocyte differentiation.
S. Tabrizifard, A. Olaru, J. plotkin, M. Fallahi-Sichani, F. Livak and H. T. Petrie (2004) Analysis of transcription factor expression during discrete stages of post-natal thymocyte differentiation, J. Immunol, in press.
A. Olaru, D. Patterson, I. Villey and F. Livak (2003) DNA-Rag protein interactions in the control of selective D gene utilization in the TCRb locus, J. Immunol, 171, 3605
F. Livak and H. T. Petrie (2002) Access roads for RAG-ged terrains: control of T-cell receptor gene rearrangement at multiple levels, Sem. Immunol., 14, 297.
F. Livak, D. B. Burtrum, L. Rowen, D. G. Schatz and H. T. Petrie (2000) Genetic modulation of T cell receptor gene segment usage during somatic recombination, The Journal of Experimental Medicine, 192, 1191-1196.
H.T. Petrie, M. Tourigny, D. B. Burtrum and F. Livak (2000) Precursor thymocyte proliferation and differentiation are controlled by signals unrelated to the pre-TCR, J. Immunol. 165, 3094-3098.
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