Overexpression of Batf induces an apoptotic defect and an associated lymphoproliferative disorder in mice

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.

BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid

“…disorder caused by increased T cell survival has been observed in aged mice overexpressing BATF (Logan et al, 2012). We observed that BATF KO CD4 + T cells were comparable BATF KO iT reg cells fail to suppress inflammation in the intestine As shown in Fig.…”

<p>Transcriptomics-Based Characterization of the Toxicity of ZnO Nanoparticles Against Chronic Myeloid Leukemia Cells</p>

“…51,52 Our transcriptomics data showed that ZnO NPs reduced the expression of genes implicated in the positive regulation of "immune response", "cell activation", "cell proliferation", "cell migration", "cell adhesion" and "signal transduction". For example, KIT, which is a key receptor whose signaling is essential for the activation, survival and proliferation of hematopoietic stem cells, 53,54 BATF, which plays significant roles in the survival and proliferation of blood cells, 55,56 and PTPRC, which is required for hemopoiesis and homing of leukemic cells to bone marrow, 57 were down-expressed following the treatment with ZnO NPs. Other interesting genes including IGF1, VEGFA and NCKAP1L, which promote the survival, proliferation and migration of cancer cells, [58][59][60][61][62][63][64] were also down-expressed in the treated cells.…”

BATF regulates the development and function of IL-17 producing iNKT cells

“…Interestingly, quantification of thymic iNKT cells in Batf ΔZ/ΔZ mice revealed a number equivalent to WT mice [2]. As the CD2-HA-BATF transgene directs BATF overexpression to all T cells (thymic and peripheral) [7], iNKT cells were re-examined and compared to numbers in WT and Batf ΔZ/ΔZ mice. The percentage of T cells positive for interaction with glycolipid-loaded CD1d tetramers was assessed by flow cytometry using single cell suspensions from thymus, spleen and PLN.…”

“…Batf ΔZ/ΔZ and CD2-HA-BATF mice expressing human, HA-tagged BATF were described previously [2,7] and were maintained by breeding to C57Bl/6 mice (Harlan, Indianapolis, IN). Experiments were performed using sex-matched littermates between 6 and 12 wk of age.…”

“…The impact of disrupting BATF function in vivo has been examined by several groups [2-5]. Mice in which BATF is overexpressed using a T cell-specific promoter display a reduced number of iNKT cells [6], an increased number of CD4 + T cells expressing IL-17 (Th17) [5] and an altered cytokine environment that promotes the gross overproduction of class switched Ig by B cells [7]. Batf null mice are viable, yet display a severe deficiency in Th17 and T follicular helper cells [2,3,5].…”