Interleukin-4 Production by Follicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V

• Published in: Immunity (Cambridge, Mass.) Vol. 36; no. 2; pp. 175 - 187
• Main Authors: Vijayanand, Pandurangan, Seumois, Grégory, Simpson, Laura J., Abdul-Wajid, Sarah, Baumjohann, Dirk, Panduro, Marisella, Huang, Xiaozhu, Interlandi, Jeneen, Djuretic, Ivana M., Brown, Daniel R., Sharpe, Arlene H., Rao, Anjana, Ansel, K. Mark
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.02.2012
• Subjects: Animals; Binding Sites - genetics; Conserved Sequence; Cytokines - genetics; Enhancer Elements, Genetic; Hypersensitivity - genetics; Hypersensitivity - immunology; Immunity, Humoral - genetics; Interleukin-4 - biosynthesis; Interleukin-4 - deficiency; Interleukin-4 - genetics; Lung - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; NFATC Transcription Factors - metabolism; Promoter Regions, Genetic; Sequence Deletion; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - immunology; Th2 Cells - immunology; Transcription, Genetic
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.12.014

Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3′ enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases. [Display omitted] ► Follicular helper T cells specifically require HS V for IL-4 production ► The Il4 enhancer HS V is indispensable for Th2 cell humoral immunity ► Th2 cell-type tissue responses are relatively independent of HS V in vivo ► HS V is essential for erasure of repressive chromatin marks from the Il4 locus