Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks

Key Points Basic leucine zipper transcription factor ATF-like (BATF), BATF2 and BATF3 are basic leucine zipper (bZIP) proteins that form heterodimers with JUN proteins. Initially, BATF family members were thought to function only as inhibitors of activator protein 1 (AP-1)-driven transcription, but recent studies using Batf -, Batf2 - and Batf3 -knockout mice have uncovered unique positive transcriptional activities for these factors in B cells, T cells and dendritic cells (DCs). BATF leucine zipper motifs interact with interferon-regulatory factor 4 (IRF4) and IRF8 at AP-1–IRF consensus elements (AICEs). The discovery of the BATF–IRF interaction adds additional flexibility to the actions of IRF4 and IRF8, which were previously known to interact with ETS factors such as PU.1 and SPIB for binding DNA. BATF3 is required for the development of CD8α + classical DCs (cDCs), which prime CD8 + T cell responses by cross-presentation. Thus, Batf3 −/− mice fail to reject immunogenic syngeneic tumours and have impaired virus-specific CD8 + T cell responses. Lymphoid-resident CD8α + DCs and non-lymphoid CD103 + CD11b − DCs are developmentally related and are both BATF3-dependent. The equivalent human DC subset expresses DC natural killer lectin group receptor 1 (DNGR1) and blood DC antigen 3 (BDCA3) and is also BATF3-dependent. BATF is required for the production of interleukin-17 (IL-17), IL-21, IL-22 and IL-23 receptor in T helper 17 (T H 17) cells. In T H 17 cells, BATF is thought to function as a 'pioneer factor' with IRF4 to mediate chromatin remodelling. Batf −/− mice have a defect in their production of isotype-switched antibodies owing to defective class-switch recombination in their B cells and a failure of their T cells to differentiate into T follicular helper (T FH ) cells. In B cells, BATF is required for the expression of activation-induced cytidine deaminase (AID) and for normal intervening heavy-chain region and constant heavy-chain region (I H –C H ) germline transcription of all isotype-switch regions. In T FH cells, BATF controls the expression of MAF, B cell lymphoma 6 (BCL-6) and IL-21, which are crucial for the development of functional T FH cells. BATF1, BATF2 and BATF3 proteins have compensatory actions with each other in several immune cell lineages; for example, C57BL/6 Batf3 −/− mice retain a population of CD103 + cDCs in the skin-draining lymph nodes that is absent in C57BL/6 Batf −/− Batf3 −/− mice. Similarly, T H 2 cells that are deficien