Characterization of the lymphoproliferative disorder associated with the over-expression of BAFT family proteins in mice
Abstract
The basic leucine zipper transcription factor, ATF-like (BATF) family of basic leucine zipper (bZIP) proteins participate in AP-1 dimers that have been shown to regulate AP-1mediated gene transcription. BATF and BATF3 are the two best characterized family members and much of this understanding comes from the study of laboratory-generated mice which over-express either BATF or BATF3 in a T cell specific manner. Along with alterations in smaller T cell subsets, these transgenic mice develop a lymphoproliferative disorder (LPD) phenotype. These studies will characterize this phenotype and propose a role for BATF in the modulation of T cell apoptosis. Older CD2-HA-BATF transgenic (Tg) and CD2-Myc-Batf3 Tg mice developed weight loss and peripheral lymphadenopathy. At one year of age, transgenic and non-transgenic littermates were necropsied and samples were evaluated histologically. 93% of CD2-HA-BATF Tg mice and 80% of CD2-Myc-Batf3 Tg mice demonstrated lymphadenopathy in at least one organ. Mesenteric lymph nodes were most commonly affected, although lymphadenopathy also was noted in other lymphoid tissues. Immunohistochemical staining of lymph node masses and evaluation of lymphocytes from CD2-HA-BATF Tg and CD2-Myc-Batf3 Tg masses by flow cytometry revealed that these lesions were composed primarily of T cells, most of which were CD4+. Molecular analyses of TCRbeta rearrangements in DNA indicate that the T cells comprising the masses did not originate from a single T-cell clone and thus are defined as an LPD rather than lymphoma. In vitro characterization of T cells from the CD2-HA-BATF Tg masses revealed that transgenic T cells have diminished proliferative capacity suggesting that an apoptotic defect was the mechanism underlying mass formation. CD2-HA-BATF Tg CD4+ T cells demonstrated impaired apoptosis, and an associated anti-apoptotic alteration in Bcl-2 family members, when subjected to an apoptosis inducing cytokine withdrawal protocol in vitro. Collectively, these studies identify a novel role for BATF in the maintenance of the peripheral T cell population and propose a novel mechanism for the development of LPD.
Degree
Ph.D.
Advisors
Taparowsky, Purdue University.
Subject Area
Molecular biology|Pathology
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