How does the immune system know friend from foe in gut bacteria?

In order to maintain health, the human immune system must distinguish between friend, or the tissues of the human body, and foe, or the invasive pathogens that cause disease. This challenge is particularly apparent in the human gut, where it is not just cells of the host, but also the trillions of bacteria that co-exist and work with them that must be treated as friendly. Now, a new study reveals one mechanism through which this delicate balance between promoting and inhibiting immune response is maintained.

The study - a collaboration between researchers in Germany and Italy - is published in the journal Nature Communications.

In their study paper, senior author Thomas Brocker, a professor and director of the Institute for Immunology at Ludwig Maximilian University (LMU) of Munich in Germany, and colleagues describe how they found one way in which immune surveillance cells are trained to spot the difference between friend and foe.

Our guts are home to a complex community of more than 100 trillion microbial cells that play an important role in health and disease. These gut-resident microbes, or gut microbiota - which with their genetic material are known as the gut microbiome - influence metabolism, nutrition, and immune function.

Scientists are discovering that disruption in the gut microbiota is linked to obesity, inflammatory bowel disease, and other gastrointestinal disorders. It has also been suggested that obesity's effect on the gut microbiome may explain its strong link with type 2 diabetes. Others have likened the uniqueness of a person's gut microbiota to that of a "DNA fingerprint," raising potential privacy concerns for participants of human microbiome research projects.

Dendritic cells promote and inhibit immune response

The new study concerns a type of cell called dendritic cells (DCs) that have evolved two distinctive - and what may appear to be opposite - roles in the human body, in that they can both promote and inhibit immune response.

DCs help to activate the immune system in response to infection, but they are also involved in actively suppressing it in certain situations. They suppress immunity by triggering induced regulatory T cells (iTregs), a type of cell that controls the development of immune tolerance.

As immunity inhibitors in the gut, DCs help to train the immune system to treat gut microbiota as friend rather than foe. They do this by internalizing proteins from the microbiota and migrating to lymph nodes associated with the gut. As they travel to the lymph nodes, the DCs break down the internalized friendly bacteria proteins into smaller pieces that become similar to "identity badges" that they wear on their cell surfaces. These identity badges are displayed with specific binding proteins that iTregs recognize, with the effect that the iTregs do not promote immune responses against proteins wearing the identity badges.

Prof. Brocker says: "We believe that these iTregs are specific for the proteins produced by natural gut bacteria."

The team explains that the migration to lymph cells by the DCs - particularly those whose cell surfaces display a protein called CD103+ - is an important part of keeping the immune system updated on the composition of the gut microbiota.

Dendritic cells have an 'alarm button'

However, what the researchers wanted to discover was how this tolerance mechanism might be switched off in an emergency. Their investigation led them to another molecule that DCs display on their cell surfaces - known as CD40 - that behaves in a similar way to an alarm button. When activated, CD40 binds to a partner molecule on the surface of another type of T cell called effector T cells, which turns DCs from inhibitors of immune response to promoters.

In tests on mice, the researchers showed that animals whose CD40 signaling was permanently switched on developed severe colitis, but no other symptoms. They found that the affected dendritic cells still migrate to the lymph nodes from the gut lining, but when they get there they commit cell suicide (apoptosis) and thus deny the regulatory T cells the opportunity to sense the identity badges of the microbiota proteins that would normally protect them from immune attack.

This results in a generalized immune response in which T lymphocytes travel to the gut lining and cause inflammation. The team found that giving the mice antibiotics that killed their gut microbiota also reduced the inflammation, and the animals survived.

The researchers now want to find out whether particular regulatory T cells are programmed for specific gut bacteria, as this study might suggest.