BATF is a basic leucine zipper transcription factor that dimerizes with the JUN proteins to direct patterns of activator protein-1 (AP-1)-mediated gene expression in the immune system [
1]. 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]. The T cell deficiencies are combined with an intrinsic B cell defect blocking the production of class switched Ig to impair the immune response of these animals to antigen challenge [
2,
3]. The dramatic consequences of altering BATF expression
in vivo provides evidence that BATF functions to coordinate immune system activities critical in autoimmunity, inflammation and the host response to pathogens.
The ability of BATF to promote the differentiation of naïve CD4
+ T cells to the Th17 lineage has been shown to rely on the formation of IRF4/BATF protein complexes that bind and transactivate a number of genes, including
Il17a/f[
8]. Interestingly, we have observed a negative influence of BATF on the development of iNKT cells [
6,
9] and therefore sought to examine how these two opposing activities of BATF may influence the development of a recently identified subset of iNKT cells that expresses IL-17 [
10‐
13]. Murine iNKT-17 cells are a CD4
- NK1.1
- population that is enriched in peripheral LN (PLN) and respond following stimulation by rapidly secreting IL-17. iNKT-17 cells express RORγt and additional markers that define them as a lineage distinct from classic iNKT cells. A role for iNKT-17 cells has been demonstrated in experimental models of airway disease, asthma and collagen-induced arthritis [
12,
14,
15]. iNKT-17 cells are over-represented in NOD mice where their influence in the pancreas exacerbates the development of diabetes [
16]. In the present study, using mouse models of BATF overexpression (
CD2-HA-BATF) and deficiency (
Batf
ΔZ/ΔZ
), we demonstrate the importance of BATF to the development of iNKT-17 cells. Despite the overall reduction in the number of iNKT cells in
CD2-HA-BATF mice, the majority express IL-17. Likewise, while peripheral iNKT cell numbers are increased in
Batf
ΔZ/ΔZ
mice, the cells are deficient in IL-17 production. These data are consistent with results in Th17 cells [
5,
17] and suggest that BATF-containing protein complexes transactivate the
Il17a/f gene in NKT cells as well. The novel finding is that the function of BATF as an IL-17 inducer is separate from its effect on cell growth since Th17 cell numbers are expanded in the presence of BATF, while iNKT cell numbers are reduced. To identify an
in vitro system that would facilitate the study of BATF-mediated gene regulatory events relevant to the iNKT cell lineage, we describe features of the DN32.D3 hybridoma [
9] that indicate similarity to the iNKT-17 lineage, including the BATF-dependent expression of
Il17a mRNA. We conclude that BATF joins RORγt as the molecular signature for all IL-17 producing cells
in vivo and represents an essential component of a nuclear protein network that could be targeted to regulate IL-17-mediated disease.