Journal Article

Compensatory dendritic cell development mediated by BATF–IRF interactions

Tussiwand, Roxane, Murphy, Theresa L., Leonard, Warren J., Wu, Xiaodi, Kretzer, Nicole M., Stallings, Christina L., Schreiber, Robert D., Lee, Wan-Ling, Weiss, Leslie A., Singh, Harinder, Sibley, L. David, Glasmacher, Elke, Edelson, Brian T., Mashayekhi, Mona, Murphy, Kenneth M., Liao, Wei, Satpathy, Ansuman T., Rotondo, Jeffrey A., Lam, Samuel S. K., KC, Wumesh, Albring, Jörn C., Li, Peng, Behnke, Michael, Aurthur, Cora T.

2012

Overview

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α + classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3 -independent pathway in mice for CD8α + dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf , which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines. The roles of BATF transcription factors in dendritic cell differentiation are studied, providing evidence for molecular compensation by related family members; compensation is based on the interaction of the BATF leucine zipper domains with IRF factors to mediate cooperative gene activation. Immune responses linked to BATF–IRF4 Kenneth Murphy and colleagues study the roles of the AP-1 transcription factor BATF in dendritic-cell differentiation — a process that primes CD8 + T-cell responses to intracellular pathogens — and provide evidence for molecular compensation by related family members. Compensation is based on the interaction of the BATF leucine-zipper domains with the interferon regulatory factors IRF4 and IRF8 to mediate cooperative gene activation. In a complementary study, Warren Leonard and colleagues provide evidence that IRF4 regulates CD4 + T-cell differentiation and T H 17 function by cooperative binding interactions with the AP-1 family members BATF and JUN. These studies point to potential new targets for manipulating key immune responses that depend on BATF–IRF4 interactions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2571 / 631/45/612/822 / 631/80/86 / Analysis / Animals / Antigen Presentation / Antigens, CD - metabolism / Basic-Leucine Zipper Transcription Factors - chemistry / Basic-Leucine Zipper Transcription Factors - deficiency / Basic-Leucine Zipper Transcription Factors - genetics / Basic-Leucine Zipper Transcription Factors - metabolism / Biological and medical sciences / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - immunology / CD8 Antigens - immunology / CD8 Antigens - metabolism / Cell development (Biology) / Cell Differentiation / Cell Line, Tumor / Cell Lineage / Compensation / Control / CTLA-4 Antigen - metabolism / Dendritic cells / Dendritic Cells - cytology / Dendritic Cells - immunology / Dendritic Cells - metabolism / Female / Fibrosarcoma - immunology / Fibrosarcoma - metabolism / Fibrosarcoma - pathology / Gene Expression Regulation / General aspects / Humanities and Social Sciences / Immune system / Immunology / Infection pathogenesis / Infectious diseases / Influence / Integrin alpha Chains - metabolism / Interferon / Interferon Regulatory Factors - deficiency / Interferon Regulatory Factors - genetics / Interferon Regulatory Factors - metabolism / Interleukin-10 - metabolism / Interleukin-12 - immunology / Interleukin-12 - metabolism / Leucine Zippers / Male / Medical research / Medical sciences / Mice / Mice, Inbred C57BL / multidisciplinary / Neoplasm Transplantation / Oncogene Protein p65(gag-jun) - metabolism / Pathogens / Physiological aspects / Protein Binding / Protein Structure, Tertiary / Protein-protein interactions / Proteins / Repressor Proteins - deficiency / Repressor Proteins - genetics / Rodents / Science / T cells / T-Lymphocytes, Helper-Inducer - cytology / T-Lymphocytes, Helper-Inducer - immunology / T-Lymphocytes, Helper-Inducer - metabolism / Toxoplasma - immunology / Transcription factors