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Allergic T_H2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4⁺ T Cells.

ABSTRACT: Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate T_H2 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 T_H2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4⁺ T (MPT) cells and their derived T_H2 (MPT_H2) 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 T_H2 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 MPT_H2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPT_H2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPT_H2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPT_H2 cells in T_H2 immune responses related to the pathogenesis of allergies.

SUBMITTER: Ogasawara T

PROVIDER: S-EPMC5904433 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Ogasawara Takashi T Kohashi Yuko Y Ikari Jun J Taniguchi Toshibumi T Tsuruoka Nobuhide N Watanabe-Takano Haruko H Fujimura Lisa L Sakamoto Akemi A Hatano Masahiko M Hirata Hirokuni H Fukushima Yasutsugu Y Fukuda Takeshi T Kurasawa Kazuhiro K Tatsumi Koichiro K Tokuhisa Takeshi T Arima Masafumi M

Frontiers in immunology 20180410

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, high ...[more]

PMID: 29696026

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Project description:RationaleT-regulatory cells (Tregs) are potent immunomodulators in allergic asthma.ObjectivesWe evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4(+)CD25(+) Tregs (NTregs) and CD4(+)CD25(-) inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroach-sensitized and -challenged mice.MethodsGFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy.Measurements and main resultsAdoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHR to methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4(+)CD25(+) T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25(-)) and lung iTregs (L25(-)) groups. Higher levels of transforming growth factor-beta and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-gamma levels were observed in lung CD4(+)CD25(+) cells from the L25(-) and S25(-) cell-recipient mice than from lung NTregs (L25(+)) and spleen NTregs (S25(+)) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels.ConclusionsTregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4(+) type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-beta, IL-10, IFN-gamma, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.

Dataset Information

Allergic T_H2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4⁺ T Cells.

Publications

Allergic T<sub>H</sub>2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4<sup>+</sup> T Cells.

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