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 4

BATF and IRF4 cooperate in the development of Th9 cells.

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BATF and IRF4 cooperate in the development of Th9 cells. Wild-type, Irf4...
Wild-type, Irf4d–lck–/–, or BatfΔZ/ΔZ naive CD4+ T cells were differentiated under Th9 polarizing conditions. (A–D) Differentiating Th9 cells were transduced with control (empty vectors expressing only Thy1.1 or hCD4), BATF-, and/or IRF4-expressing retroviruses. After 5 days of differentiation, cells were stimulated with PMA and ionomycin for 5 hours before intracellular staining for IL-9 and IL-4. Dot plots (D) are gated on cells that were double-positive for Thy1.1 and human CD4. Numbers indicate the average percentage ± SD of at least three mice. (E) ChIP assays were performed for BATF and IRF4 binding to the Il9 promoter in Th2 and Th9 cells. (F) ChIP assay of IRF4 binding to the Il9 promoter in wild-type and BATF-deficient Th9 cells. (G) ChIP assay of BATF binding to the Il9 promoter in wild-type and IRF4-deficient Th9 cells. (H) Reporter assay of wild-type and mutant IL9 promoter luciferase reporter vector cotransfected into HEK293 cells with vectors expressing BATF and IRF4. Mean ± SD of four experiments. (I) ChIP assay of PU.1 binding to the Il9 promoter in wild-type and BATF-deficient Th9 cells. (J) ChIP assay of BATF and IRF4 binding to the Il9 promoter in wild-type and Batf transgenic Th9 cells. (K) ChIP assay of BATF binding to the indicated gene promoters in wild-type and IRF4-deficient Th9 cells. All ChIP data represent the average ± SD of at least three experiments. *P < 0.05; **P < 0.01.