09:33am Monday 21 August 2017

Gene appears to “skew” production of helper T cells

Encoded by Jmjd3, the enzyme Jmjd3 is one of dozens of histone demethylases that shapes chromosome architecture and indirectly affects whether genes can be expressed. Led by Houston Methodist Research Institute Center for Inflammation and Epigenetics Director Rongfu Wang, Ph.D., the research team reported in Nature Communications that the absence of Jmjd3 appears to “skew” the production of helper T cells that assist the body’s response to infection. Their studies were conducted in mice and human cell cultures.

“Our experiments specifically demonstrated that Jmjd3 deletion affected master regulators and epigenetic modifiers of T cell fate,” said Wang, the study’s principal investigator.

Without Jmjd3, the scientists found progenitor white blood cells were more likely to become Th2 and Th17 helper T cells in the small intestine and colon, and less likely to become Th1 cells — even in a mouse model where Th1 cell production should remain high. All the helper T cells are imbued with the surface protein CD4, which is added to mature helper T cells before they help the body fight any variety of infections. Such cells are called “CD4+” because their cell membranes are dotted with the protein, to which a branched sugar chain is attached.

In separate experiments using human cell cultures, the scientists found progenitor cells were more likely to become Th2 and not Th1 cells.

Th1 helper T cells aid in attacking host cells that have already been infiltrated by protists, like the malarial parasite, and bacteria. Th2 and Th17 helper T cells attack external parasites, in the blood or attached to the outside of host cells, with Th17 specifically targeting bacterial and fungal invaders and Th2 being more of a generalist. These helper T cells also play roles in cancer and autoimmunity disorders.

“Regulation of T cell differentiation is essential to maintain the appropriate balance among T cell subsets to support immune balance and to prevent autoimmunity,” Wang said. “Understanding the mechanisms of how molecules, such as Jmjd3, regulate T cell differentiation will help define epigenetic influences. This will inevitably lead to the development of innovative and effective strategies to intervene in T cell-associated diseases.”

At this early stage, it is hard to know how exactly this new knowledge about Jmjd3 might be manipulated to help the body fight off specific infections or to help the immune system recognize cancer cells and leave healthy host cells alone. But Wang said similar efforts underway in other laboratories provide some ideas.

“Clinical trials using inhibitors of other epigenetic modifiers are currently being conducted to, for example, treat patients with acute myeloid leukemia,” Wang said. “Epigenetic modifiers, such as tranylcypromine, can be tested for their ability to inhibit Jmjd3. Also, small molecules can be designed or screened for their ability to inhibit Jmjd3. We envision that in collaboration with colleagues at the Houston Methodist Research Institute Department of Nanomedicine, we could conduct a study in which we administer inhibitors using non-toxic and degradable nanoparticles, which can be targeted to specific cells or tissues, to treat cancer or autoimmune diseases.”

Wang said that future studies of Jmjd3 will explore its presumed and numerous interactions with other factors that influence its behavior as well its broader impacts on gene expression patterns.

“It appears Jmjd3 regulates specific gene expression through interactions with other gene expression modifiers and epigenetic proteins, forming stable complexes capable of binding to specific genes,” he said. “Further experiments are needed to precisely understand these mechanisms.”

Also contributing to the Nature Communications paper were Qingtian Li, Jia Zou, Mingjun Wang, Xilai Ding, Xikun Zhou, Wei Zhao, Jun Cui, and Helen Y. Wang (Houston Methodist Research Institute), Iouri Chepelev (Cincinnati Children’s Hospital Medical Center), Gang Wei (Chinese Academy of Sciences, Shanghai), and Keji Zhao (National Heart, Lung, and Blood Institute). It was funded with grants from the National Institutes of Health and the Houston Methodist Research Institute.

To speak with Rongfu Wang, please contact David Bricker, Houston Methodist, at 832-667-5811 or dmbricker@houstonmethodist.org.

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