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

BACKGROUND: BATF plays important roles in the function of the immune system. Batf null mice are deficient in both CD4+ Th17 cells and T follicular helper cells and possess an intrinsic B cell defect that leads to the complete absence of class switched Ig. In this study, Tg mice overexpressing BATF in T cells were used together with Batf null mice to investigate how altering levels of BATF expression in T cells impacts the development and function of a recently characterized population of iNKT cells expressing IL-17 (iNKT-17). RESULTS: BATF has a direct impact on IL-17 expression by iNKT cells. However, in contrast to the Th17 lineage where BATF activates IL-17 expression and leads to the expansion of the lineage, BATF overexpression restricts overall iNKT cell numbers while skewing the compartment in vivo and in vitro toward an iNKT-17 phenotype. CONCLUSIONS: This work is the first to demonstrate that BATF joins RORγt as the molecular signature for all IL-17 producing cells in vivo and identifies BATF as a component of the nuclear protein network that could be targeted to regulate IL-17-mediated disease. Interestingly, these studies also reveal that while the Il17a gene is a common target for BATF regulation in Th17 and iNKT-17 cells, this regulation is accompanied by opposite effects on the growth and expansion of these two cell lineages.

Batf promotes growth arrest and terminal differentiation of mouse myeloid leukemia cells.

Batf is a basic leucine zipper transcription factor belonging to the activator protein-1 superfamily. Batf expression is regulated following stimulation of both lymphoid and myeloid cells. When treated with leukemia inhibitory factor, mouse M1 myeloid leukemia cells commit to a macrophage differentiation program that is dependent on Stat3 and involves the induction of Batf gene transcription via the binding of Stat3 to the Batf promoter. RNA interference was employed to block Batf induction in this system and the cells failed to growth arrest or to terminally differentiate. Restoring Batf expression not only reversed the differentiation-defective phenotype but also caused the cells to display signs of spontaneous differentiation in the absence of stimulation. Efforts to define genetic targets of the Batf transcription factor in M1 cells led to the identification of c-myb, a proto-oncogene known to promote blood cell proliferation and to inhibit the differentiation of M1 cells. These results provide strong evidence that Batf mediates the differentiation-inducing effects of Stat3 signaling in M1 cells and suggest that Batf may play a similar role in other blood cell lineages where alterations to the Jak-Stat pathway are hallmarks of disrupted development and disease.