Isoforms of Human Terminal Transferase and Lymphopoiesis

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Terminal deoxynucleotidyl transferase (TdT) is a key nuclear enzyme that is involved in the generation of diversity of T cell (TCR) and immunoglobulin B receptors (BCR). TdT is expressed at lower levels in fetal sites of lymphocyte generation, however, it is a normal component involved in the rearrangement process resulting in the production of diverse receptors in the adult. The lack of TdT activity during early development contributes to the generation of T and B cell repertoires that are less diverse than their adult counterparts. There is evidence in mice and now in man that there are alternative isoforms of TdT which have distinct and opposite activities in controlling the CDR3 lengths of T and B cell receptors. Since, virtually nothing is known about the normal patterns of expression of human TdT isoforms, the cellular and molecular aspects of TdT isoform expression by T and B cells will be studied during fetal and adult life. New monoclonal antibodies will be raised to the TdT isofroms which will permit a detailed survey of expression of these forms in normal and abnormal T and B cell development. The functional relationships of the splice variants of TdT will be analyzed and the hypothesis will be tested that the isoforms perform distinct but complementary functions during lymphocyte development. TdT activity is clearly important in the generation of diversity in both T and B cells and further elucidation of the mechanism of its action and control of expression are key to our understanding of the development of diversity in the immune system. TdT is also expressed at high levels in certain lymphoid malignancies and shares some structural characteristics with the DNA modifying family of proteins such as BRCA1, 53BP1 so that the alternative forms of TdT may play a role in tumorigenesis. The novel reagents we plan to make, together with new insights we obtain in the analysis of normal development, will permit us to analyze in more detail the expression and function of TdT in human lymphoid cells and the regulation and role of TdT expression in human leukemia and lymphoma.