Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells.

Takashi Ogasawara,Koichiro Tatsumi,Kazuhiro Kurasawa,Jun Ikari,Takeshi Tokuhisa,Takeshi Fukuda,Hirokuni Hirata,Lisa Fujimura,Haruko Watanabe-Takano,Yasutsugu Fukushima,Akemi Sakamoto,Masafumi Arima,Nobuhide Tsuruoka,Yuko Kohashi,Toshibumi Taniguchi,Masahiko Hatano

doi:10.3389/fimmu.2018.00750

Abstract

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3′ distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies.

Highlights

Allergic asthma is an inflammatory airway disorder mediated by TH2 cells, which produce various effector cytokines (IL-4, IL-5, and IL-13) [1, 2]
Tissue hypereosinophilia occurs with increased IL-4, IL-5, and IL-13 production in B-cell lymphoma 6 (Bcl6)-knockout (KO) mice, suggesting that Bcl6 participates in allergy pathogenesis and that it may be important for reducing TH2 immune responses
The absolute numbers and percentages of IL-4+ memory phenotype CD4+ T (MPT) cells were negatively associated with Bcl6 levels (Figure 1G), whereas the absolute numbers of green fluorescent protein (GFP)+ MPT cells (Figure 1H) and MPT cells (Figure 1I) among all CD4+ T cells were positively correlated with Bcl6 levels

Summary

Introduction

Allergic asthma is an inflammatory airway disorder mediated by TH2 cells, which produce various effector cytokines (IL-4, IL-5, and IL-13) [1, 2]. Tissue hypereosinophilia occurs with increased IL-4, IL-5, and IL-13 production in B-cell lymphoma 6 (Bcl6)-knockout (KO) mice, suggesting that Bcl participates in allergy pathogenesis and that it may be important for reducing TH2 immune responses. Reported that Bcl repressed Il4 and Il5 expression by binding to genomic DNA in naïve CD4+ T cell-derived memory (NAM) TH2 cells [14, 15], identifying Bcl as a critical regulator of TH2 cytokine production in memory CD4+ T cells in addition to its role in the maintenance and survival of the cells [15,16,17]. CNS2-active MPT cells are candidate cells that initially produce IL-4 to promote TH2 cell differentiation, and they may be involved in allergy pathogenesis, the mechanisms remain unclear. Because Bcl expression is extremely high in CNS2-active MPT cells [29], we hypothesized that Bcl regulates allergen-mediated MPT cell activation in TH2 cell-dependent allergies

Methods

Results

Conclusion