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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #342896
Research Project: Molecular Approaches to Control Intestinal Parasites that Affect the Microbiome in Swine and Small Ruminants

Location: Animal Parasitic Diseases Laboratory

Title: Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma

Author
item LORENTSEN, K.J. - University Of Florida
item CHO, J.J. - University Of Florida
item LUO, X - University Of Florida
item ZUNIGA, AN - University Of Florida
item Urban, Joseph
item ZHOU, L - University Of Florida
item GHARAIBEH, R - University Of Florida
item JOBIN, C - University Of Florida
item KLADDE, MP - University Of Florida
item AVRAM, D - University Of Florida

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/3/2018
Publication Date: 4/26/2018
Citation: Lorentsen, K., Cho, J., Luo, X., Zuniga, A., Urban Jr, J.F., Zhou, L., Gharaibeh, R., Jobin, C., Kladde, M., Avram, D. 2018. Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma. Nature Communications. 9(1)1679. https://doi.org/10.1038/s41467-018-04111-0.
DOI: https://doi.org/10.1038/s41467-018-04111-0

Interpretive Summary: Worm parasites can infect humans and animals and stimulate production of immune proteins including messenger molecules called cytokines and antibodies that are specific for the infection. Scientists from ARS Beltsville and the University of Florida in Gainesville showed that there is a genetic transcription factor called Bcl11b that is important in stimulating an immune lymphocyte Th2 cell lineage important in the response to worms and related responses to allergens. This factor is responsible for the regulation of accessibility in the host cell genome that expresses an important cytokine called interleukin-4 or IL4. This, in turn, regulates the expression of other cytokines in the cascade that result in expression of the anti-worm response or exacerbated responses to allergens that can result in allergic disease expression. Further studies in this model could provide scientists and clinicians the tools to reduce the level of allergic disease in humans and animals while promoting the elimination of the worms from the host.

Technical Abstract: Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection with a major reduction of Th2 cytokines and Gata3. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) associates with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binds to and restricts chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; (3) restricts Runx3 expression by association with a regulatory region 5' of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), IL13 and IL5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.