Antigen receptor gene assembly bygene assembly by T and B lymphocytes is a fundamental aspect of adaptive immunity and is required to generate a diverse repertoire of immunoglobulins and I cell receptors, which recognize virtually any pathogen a species may encounter. The processes involved in the ordered assembly of antigen receptor genes by V(D)J recombination is catalyzed by the RAG-I and RAG-2 enzymes, which are uniquely expressed in precursor T and B lymphocytes. However, the mechanisms controlling Ragi and Rag2 gene expression or ontogeny We developed a congenic strain (ZORI, """"""""Zfp608 over-expressing Rag insufficient"""""""") with defects in Ragi and Rag2 expression, thymocyte maturation, and peripheral T cell homeostasis. This mutation maps to a chromosome 18 locus containing a single known gene, Zfp608. In wildtype mice, the Zfp608 gene is highly expressed in neonatal thymus but is extinguished after birth. In contrast, ZORI mice sustain thymocyte expression of Zfp608 throughout life. The ZORI mutation produces a thymocyte-intrinsic developmental defect. Over-expression of Zfp608 in normal thymocytes severely impairs Rag expression, providing an underlying mechanism for the defect in ZORI thymocyte development. Thus, the normal function of Zfp608 may be to prevent Rag expression during prenatal and early postnatal development. Our results raise several questions about the mechanisms of Zfp608 regulation and function that we will address in this research proposal. First, how is Zfp608 regulated during ontogeny and what accounts for defective Zfp608 expression in ZORI mice? Second, we hypothesize that targeted deletion of Zfp608 may Rag of to development of the immune aims are I) to examine the role of Zfp608 in thymocyte ontogeny and development, and 2) explore the impact of Zfp608 deficiency on fetal/postnatal development and the adaptive immune response. Project Summary Antigen receptor gene assembly by T and B lymphocytes is a fundamental aspect of adaptive immunity and repertoire immunoglobulins and T recognize virtually The involved 1 uniquely and B lymphocytes. Rag1 during lymphocyte development or mammalian ontogeny are incompletely understood. """"""""Zfp60S over-expressing Rag insufficient"""""""") with Rag1 thymocyte maturation, peripheral cell homeostasis. 1S gene, Zfp60S. Zfp60S highly neonatal is extinguished after birth. ZORI mice sustain thymocyte Zfp60S throughout life. The ZORI mutation Zfp60S in normal thymocytes severely impairs Rag expression, providing an underlying for in ZORI thymocyte Zfp60S may be to during prenatal and early postnatal development. questions of Zfp60S will research proposal. Zfp60S regulated Zfp60S Second, we hypothesize that targeted deletion Zfp60S may result in de-repression of Rag genes and premature expansion of T cell subsets, which may provide a model to understand why development of the immune system is delayed in ontogeny compared to development of other organ systems.
Our specific aims are 1) to examine the role of Zfp60S in thymocyte ontogeny and development, explore the impact of Zfp60S deficiency on fetal/postnatal development and the adaptive immune
Antigen receptor gene assembly by T and B lymphocytes, catalyzed by the RAG enzymes, is a fundamental property of adaptive immunity and is required to generate a diverse repertoire of immunoglobulins and T cell receptors, which recognize virtually any pathogen a species may encounter. We have identified a novel zinc finger protein, Zfp608 that negatively regulates Rag expression in developing T lymphocytes. In this proposal, we plan to elucidate mechanisms of Zfp608 regulation during ontogeny, mechanisms of Zfp608-mediated Rag repression, and the impact of targeted deletion of Zfp608 on development of the adaptive immune system.
| Reed, N P; Henderson, M A; Oltz, E M et al. (2013) Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609. Genes Immun 14:7-12 |
| Sikes, Michael L; Oltz, Eugene M (2012) Genetic and epigenetic regulation of Tcrb gene assembly. Curr Top Microbiol Immunol 356:91-116 |
