Abstract
Activator protein-1 (AP-1) is a dimeric transcription factor composed of the Jun, Fos and Atf families of proteins. Batf is expressed in the immune system and participates in AP-1 dimers that modulate gene expression in response to a variety of stimuli. Transgenic (Tg) mice overexpressing human BATF in T cells were generated using the human CD2 promoter (CD2-HA (hemagglutinin antigen) - BATF). By 1 year of age, over 90% of the mice developed a lymphoproliferative disorder (LPD). The enlarged lymph nodes characteristic of this LPD contain a polyclonal accumulation of T cells with a CD4+ bias, yet efforts to propagate these tumor cells in vitro demonstrate that they do not proliferate as well as wild-type CD4+ T cells. Instead, the accumulation of these cells is likely due to an apoptotic defect as CD2-HA-BATF Tg T cells challenged by trophic factor withdrawal in vitro resist apoptosis and display a pro-survival pattern of Bcl-2 family protein expression. As elevated levels of Batf expression are a feature of lymphoid tumors in both humans and mice, these observations support the use of CD2-HA-BATF mice as a model for investigating the molecular details of apoptotic dysregulation in LPD.
Highlights
Results show that increased expression of Batf in T cells impacts signaling important to the proper development of thymic NKT cells[8,9] and that the loss of Batf has a dramatic impact on the differentiation of CD4 þ, IL–17-producing
We have utilized a line of Tg mice in which the human BATF protein is expressed constitutively in both thymic and peripheral T cells to test the impact of long-term, chronic BATF overexpression on T-cell maturation and homeostasis
It was important to establish that the CD2-hemagglutinin antigen (HA)-BATF transgene continues to be expressed in peripheral T cells and that T-cell receptor (TCR) signaling in Tg T cells remains intact and properly induced by Activator protein-1 (AP-1) complexes containing BATF
Summary
Tg mice expressing hemagglutinin antigen (HA) -epitope tagged human BATF protein in T cells (CD2-HA-BATF) have been described previously in conjunction with a study that demonstrated a direct role for BATF in regulating thymocyte proliferation in vitro.[14]. In the absence of stimulation, the Tg nuclear extract showed increased AP-1 activity resulting from the formation of DNA-binding heterodimers containing human BATF and the Jun proteins expressed in resting T cells. The presence of BATF is demonstrated by the higher molecular weight complexes detected following the addition of polyclonal anti-BATF or monoclonal anti-HA antiserum to the reaction (Figure 1b, complexes 1 and 2, respectively) These results validate use of the Tg, CD2-HA-BATF mouse model to study the long-term impact of BATF expression on peripheral T-cell function. Tg T cells show a statistically significant bias toward CD4 þ cells (Figure 1d, right panel) These findings are consistent with the reduced percentage of splenic CD4 þ T cells noted previously in Batf null (BatfDZ/DZ) mice.[10]. In order to determine how BATF overexpression influences T-cell homeostasis, CD2-HA-BATF Tg mice, along with their
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