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Policing the Immune System

Not all T-reg cells are equally effective in policing immune responses.

Not all T-reg cells are equally effective in policing immune responses. Credit: iStockphoto

By Erika Cretney and Stephen Nutt

The discovery of cells that regulate the body’s immune response will help scientists to interpret the effectiveness of newly developed drugs and have wide-ranging repercussions for the treatment of conditions including cancer and multiple sclerosis.

The immune system is an intricate network of cells, proteins, tissues and organs that work together to protect our body from disease. Should a foreign invader such as a bacterium or a virus dare to enter our body, an impressive multi-layered defence is in place to ensure its elimination. Subsequently an immunological memory develops, enabling the body to recall previous attacks and mount an even quicker and more powerful response each and every time that particular type of foreign invader is encountered.

The cellular component of the immune system comprises a range of cell types that are responsible for the activation, execution and termination of immune responses. T cells play a central role in the immune system, and are a perfect example of the complexity of the immune network.

T cells exist in many flavours. Killer T cells can directly kill infected and diseased cells; helper T cells cannot kill cells directly but help to stimulate the activity of other immune system cells; and memory T cells hang around in small numbers after an attack on the body and expand quickly in response to subsequent attacks.

Maintaining an effective immune system is a real balancing act as there is only a fine line between the immune system doing its job effectively and the immune system being overly responsive and causing collateral damage to the body’s own tissues. For example, the avian influenza (bird flu) virus causes the immune system to become overly reactive, resulting in a vicious assault on the lungs by the patient’s own immune cells. Ultimately the virus causes the patient’s immune system to kill the patient rather than the virus itself.

Regulating the Immune System
Regulatory T (Treg) cells are like the immune system’s police force, and are essential to balance immune responses. They function by suppressing or blocking immune system activity, making sure that the immune system does not mount a response against the body’s own tissue.

So what happens when Treg cells are out of whack? The immune system becomes unbalanced, causing many problems. People with Treg cell deficiency develop a rare syndrome called IPEX. In these patients, their immune system goes haywire and they suffer an autoimmune attack on multiple organs, causing most patients to die before the age of two.

A bone marrow transplant is the only cure for patients with IPEX syndrome. This replaces all the patient’s immune cells, including the Treg cells, but it needs to be undertaken at an early age before irreversible autoimmune damage to organs has occurred.

In a healthy individual, Treg cells suppress autoimmune T cells, preventing damage from occurring and ensuring that the body’s immune system remains in a happy balance. Mice that lack Treg cells develop a similar disease to IPEX patients, but this can be cured by injecting healthy Treg cells into these animals.

While a lack of Treg cells in humans results in devastating disease, too many Treg cells can also be problematic. For example, increased numbers of Treg cells is linked to poorer survival in cancer patients. The excess Treg cells inhibit the body’s normal arsenal of anti-cancer immune responses by blocking the infiltration of T cells into the tumour.

Indeed, if Treg cells are the police force of the immune system there appear to be “good cops” that play a beneficial role by suppressing autoimmune disease, controlling inflammation and preventing transplant rejection, and “bad cops” that play a deleterious role by restricting anti-tumour and anti-microbial immunity.

Only Some Cells Are Active
Our research team is interested in how immune functions are programmed in cells. This programming relies on transcription factors that bind to genes and regulate their activity. One such transcription factor, B lymphocyte-induced maturation protein-1 (Blimp-1), controls the function of many cell types in the immune system – including T cells and B cells.

Our research group has discovered that Blimp-1 is present in some (but not all) Treg cells. We have discovered that, at least in the mouse, the bulk of Treg cells kack Blimp-1, are inactive and serve as a reservoir of these crucial cells for future use. In contrast, we found that a small subset of Treg cells that contain Blimp-1 appear to be active Treg cells that are crucial to immune response regulation.

So what makes this new population of active Treg cells so special? Our experiments revealed that active Treg cells in the mouse are unique in their ability to produce interleukin-10 (IL-10). IL-10 secretion is one of the major mechanisms by which Treg cells block or suppress other cell types.

We found that these active Treg cells are mostly located at sites that have direct contact with the environment, such as the gut (which is exposed to everything we ingest) and the lungs (which are exposed to the air and any pathogens we might breathe in). Given the huge number of harmless microorganisms that are encountered at these sites, it is not surprising that they contain many active Treg cells – production of IL-10 in the gut and lungs prevents unnecessary immune responses against harmless microorganisms.

Furthermore, a team led by Nabila Seddiki of the National Centre for HIV Epidemiology and Clinical Research, University of NSW (currently at the Université Paris-Est Créteil, France) recently discovered Blimp-1-containing Treg cells in humans. We believe that these are the human-equivalent of the active Treg cells we identified in mice. Like their mouse counterparts, the human active Treg cells produce high amounts of IL-10 and may also be the key regulators of the immune response regulation in humans.

Clinical Interest
Because of the crucial role that Treg cells play in maintaining balance in the immune system, there is significant interest in the application of our understanding of Treg cells to help fight disease. More than 200 clinical trials involving Treg cells have been initiated.

The role of Treg cells in fighting cancer is emerging as a significant field in oncology. Cancer cells employ several strategies to evade the immune system. For example, some cancers secrete suppressive proteins that block immune responses, or make themselves invisible to the immune system by modifying proteins on their cell surface. Other cancers make proteins that protect the cell from dying by blocking immune-activated death pathways within the cell.

Some tumours can even increase the number of Treg cells in the body. These Treg cells act as efficient bodyguards for the cancer by blocking tumour-infiltrating cells and preventing them from adequately fighting the cancer. A number of clinical trials are currently examining the therapeutic potential of drugs that specifically delete Treg cells in patients with cancers, including hepatocellular carcinoma, melanoma, ovarian cancer, lymphoma and breast cancer.

Because of the pivotal role that Treg cells play in regulating the immune system, Treg cell numbers are also being used as an indicator of prognosis, and to predict responses in clinical trials for a variety of diseases including cancer, psoriasis, Crohn’s disease, uveitis, multiple sclerosis and food allergy, as well as in organ transplant recipients.

Potential Therapies
So what impact does our discovery of active Treg cells have on clinical trials involving Treg cells? Given that active Treg cells appear to exist in humans, we believe our findings will have a huge impact on the interpretation of many studies. Our research suggests that while the majority of Treg cells present in the body are in a resting state, a small but highly effective group of active Treg cells can be recruited to effectively police the immune response.

This suggests that drugs that specifically deplete the active Treg cells may represent excellent candidates as therapies for cancer patients. Furthermore, strategies that manipulate this active Treg cell population could also restore the balance in auto­immune diseases.

The identification of active Treg cells will also impact on clinical trials where Treg cells are being used as an indicator of prognosis or to identify responders to treatment, as the size of the total Treg cell pool might not be as informative a measure as the number of just the active Treg cells in a patient.

In clinical trials where donor Treg cells are injected into transplant recipients to prevent graft-versus-host disease, our data suggest that the properties of the Treg cells being transferred will be important. The active Treg cell subset might be more effective in suppressing disease in these patients than the general pool of Treg cells currently being infused in these trials.

Maintaining an effective immune system is a balancing act that has evolved over millions of years with many built-in safety features. Our finding that not all Treg cells are equally effective in policing immune responses will focus the way that researchers look at immune responses, and could have wide-ranging repercussions for the treatment of autoimmune diseases, organ transplantation and cancer, and change how the efficacy of newly developed drugs is measured.

Armed with our knowledge that the active Treg cell subset are the key drivers of immune regulation, we hope to finally have an edge that will allow us to tip the balance in the body’s favour.

Erika Cretney is a Senior Postdoctoral Fellow and Stephen Nutt is Division Head in the Molecular Immunology Division at The Walter and Eliza Hall Institute of Medical Research.