Researchers identify key molecule involved in immune regulation

The majority of the molecules in human bodies support the immune system to keep individuals healthy but they do so without reacting excessively, as this may otherwise drive the immune cells to cause problems, like autoimmune disorders.

Autoimmune Disease

Autoimmune Disease. Image Credit: nelzajamal/Shutterstock.com

One specific molecule, known as AIM2, is part of the human’s inherent immunity—a defense mechanism that was established since birth—to combat the invading pathogens and keep people healthy.

However, not much was known about the role played by the AIM2 molecule in T cell adaptive immunity—that is, defenses created in response to health problems and specific pathogens developed by humans over the course of their lives.

Researchers from the University of North Carolina (UNC) School of Medicine, jointly headed by Jenny Ting, Ph.D., the William Kenan Distinguished Professor of Genetics, and Yisong Wan, PhD, professor of microbiology and immunology, have now discovered that the AIM2 molecule is crucial to ensure the proper function of regulatory T cells, also called Treg cells, and has an important role to play in alleviating autoimmune disorders.

Treg cells are essentially a seminal group of adaptive immune cells that inhibits an overzealous immune reaction, like those occurring in autoimmune disorders.

The study revealed that more than in the innate immune cells, the AIM2 molecule is essentially expressed at a relatively higher level in Treg cells of the adaptive immune system. The study was published in the Nature journal.

Our study unveils an unexpected and previously unappreciated role for AIM2 in Treg cells in adaptive immunity, which is independent of AIM2’s classic function in the innate immunity.”

Jenny Ting, PhD, Study Co-Senior Author and Member of Lineberger Comprehensive Cancer Center, University of North Carolina

Ting is also the director of the Center for Translational Immunology.

Wan, the co-senior author of the study and a member of the UNC Lineberger Comprehensive Cancer Center, stated, “Because Treg cells are well-known players in a broad range of diseases including autoimmunity, inflammation, and cancers, our findings will help us identify new molecular targets and develop new therapeutic strategies to test against debilitating and fatal diseases.”

Normal immune reactions are performed by both adaptive immunity and innate immunity to combat the invading pathogens and sustain biological stability. However, such responses should be controlled so that they do not intensify and lead to a range of different health issues apart from what the pathogen initially caused. Discrete roles are played by distinct molecules and cell types in the down-regulation of adaptive immunity and innate immunity.

The study demonstrates that the AIM2 molecule, within the Treg cells, is one of them. Treg cells tend to mitigate the over-exuberant immune reactions, and hence, they are crucial to ensure the check-and-balance of the innate immunity system.

The defective function of Treg cells usually disrupts the stability of the immune system and can lead to inflammatory and autoimmune diseases.

In laboratory experiments headed by Wei-Chun Chou, PhD, the first author of the study and a research associate in the Ting Lab, the UNC team discovered that the AIM2 molecule was expressed at a relatively higher level in Treg cells than in the inherent immune cells, in both human beings and mice.

This suggests a big role for AIM2 in Treg cells. We found that AIM2 is important to maintain the normal function of Treg cells, which could not effectively protect mice from developing autoimmune encephalomyelitis and inflammatory colitis without AIM2.”

Wei-Chun Chou, PhD, Study First Author and Research Associate, Lineberger Comprehensive Cancer Center, University of North Carolina

Both these conditions are models of colitis and multiple sclerosis—the human diseases.

We conducted further molecular and biochemical analysis to reveal a new, cellular signaling pathway of protein molecules in Treg cells—called the AIM2-RACK1-PP2A-AKT pathway—which regulates the metabolism and function of Treg cells to mitigate autoimmune disease,” Chou added.

Essentially, AIM2 restrains AKT phosphorylation, an important biological process but one that needs to be regulated.”

Zengli Guo, PhD, Study Co-First Author and Research Associate, Lineberger Comprehensive Cancer Center, University of North Carolina

Guo also works in the UNC Department of Microbiology and Immunology,

Because of these studies, the team is hoping to alter the function or expression of molecules in the AIM2 signaling pathway in human Treg cells to ultimately influence the outcome of various diseases, like autoimmune disorders or cancer.

Source:
Journal reference:

Chou, W-C., et al. (2021) AIM2 in regulatory T cells restrains autoimmune diseases. doi.org/10.1038/s41586-021-03231-w.

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