Th9 cell development requires a BATF-regulated transcriptional network
Rukhsana Jabeen, Ritobrata Goswami, Olufolakemi Awe, Aishwarya Kulkarni, Evelyn T. Nguyen, Andrea Attenasio, Daniel Walsh, Matthew R. Olson, Myung H. Kim, Robert S. Tepper, Jie Sun, Chang H. Kim, Elizabeth J. Taparowsky, Baohua Zhou, Mark H. Kaplan
Rukhsana Jabeen, Ritobrata Goswami, Olufolakemi Awe, Aishwarya Kulkarni, Evelyn T. Nguyen, Andrea Attenasio, Daniel Walsh, Matthew R. Olson, Myung H. Kim, Robert S. Tepper, Jie Sun, Chang H. Kim, Elizabeth J. Taparowsky, Baohua Zhou, Mark H. Kaplan
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Research Article Immunology

Th9 cell development requires a BATF-regulated transcriptional network

Abstract

T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor–like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.

Authors

Rukhsana Jabeen, Ritobrata Goswami, Olufolakemi Awe, Aishwarya Kulkarni, Evelyn T. Nguyen, Andrea Attenasio, Daniel Walsh, Matthew R. Olson, Myung H. Kim, Robert S. Tepper, Jie Sun, Chang H. Kim, Elizabeth J. Taparowsky, Baohua Zhou, Mark H. Kaplan

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Figure 3

Transcription factor regulation of Th9-associated genes.

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Transcription factor regulation of Th9-associated genes. Naive CD4+ T ce...
Naive CD4+ T cells from mice of the indicated genotypes were differentiated under Th9 conditions. (A) Supernatants were isolated following anti-CD3 stimulation for 24 hours, and cytokine concentration was determined by ELISA. ND, not detected. (B) RNA was isolated from Th9 cells of each genotype for expression analysis of the indicated genes using qRT-PCR. Expression is relative to wild-type Th9 cells. Data are the average ± SD of three to six experiments. (C–E) Naive CD4+ T cells were isolated from wild-type and BATF-deficient mice and differentiated under Th9 polarizing conditions before analysis of IL-9 production using intracellular cytokine staining (C), ELISA following 24-hour stimulation with anti-CD3 (D) and qRT-PCR of mRNA following 6 hours of stimulation with anti-CD3 (E). (F and G) Naive CD4+ T cells from wild-type and Batf transgenic mice were differentiated under Th9 polarizing conditions before analysis of IL-9 production using intracellular cytokine staining (F) and ELISA following 24-hour stimulation with anti-CD3 (G). (H) RNA was isolated from wild-type and BATF-deficient Th9 cells for expression analysis of the indicated genes using qRT-PCR. (I) Supernatants were isolated following anti-CD3 stimulation for 24 hours and tested for cytokine concentration by ELISA. For all data, *P < 0.05; **P < 0.01; ***P < 0.0001. (J) Diagram summarizing transcription factor regulation of genes in Th9 cells. Genes regulated by each transcription factor are within each box color-coded to the transcription factor. §Negatively regulated by IRF4; §§negatively regulated by IRF4 and STAT6.