Regulatory T Cells (Tregs) and Immune System

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Table of Contents

Mechanism
Autoimmunity
Cancer and Infectious Diseases
Analysis
Conclusion
Works Cited

Regulatory T cells (Tregs) play an important role in maintaining a healthy immune system. Beginning in the 1990s, researchers began classifying a new group of T cells that is now known as regulatory T cells. There is therefore a need to fully understand the mechanism that allows Tregs to inhibit the hyperactivity of T cells that can be both beneficial as well as cause significant damage to the human body. Understanding the action of Tregs is not only important when it comes to preventing autoimmune diseases, it can also be used to solve the problem of organ transplants. On the other hand, knowledge of both Tregs and T cells can increase the ability of man to prevent not only harmful infections but also the prevention of cancer and other abnormal cell growth.

Mechanism

It is imperative that there must be a balance between immunity and tolerance in order to maintain immune homeostasis (Taams & Akbar, p. 115). This has been clearly framed by researchers from the Department of Experimental Pathology, Kyoto University when they asserted that, “The mammalian immune system protects the host from a broad range of pathogenic micro-organisms while avoiding misguided or excessive immune reactions that would be deleterious to the host” (Sakaguchi et al., p. 775). A weak immune response will make the body susceptible to diseases as well as increasing the risk for cancer and related problems. On the other hand an overly active immune response will cause unwanted damage to human tissues. There is therefore great importance in striking the correct balance between immunological self-tolerance and the strengthening of weak immune responses (Sakaguchi et al., p. 775).

The mammalian immune system uses a complex mechanism that aids in the destruction of micro-organisms as well as the eradication of tumours. When the body is infected by bacteria and other harmful organisms, the lymph nodes as well as the other components of the immune system will be activated to ward off the external threat. The same mechanism is in effect within the body as abnormal growth of cells are kept in check so as to prevent the unmitigated increase in unwanted cells that can further develop into cancerous cells. If the system is as simple as the one described above then it would be best to increase the ability of T cells so that it can be more effective in guarding the body from these threats. The only problem is that without a regulator, T cells can turn against its host and attack normal tissues resulting in autoimmune diseases such as Type 1 diabetes, allergies and asthma.

Aside from the need to regulate the destructive capabilities of T cells – when it comes to its main function as the body’s first line of defence against pathogens – there is also the need to regulate its impact when it comes to minimising the body’s rejection on transplanted organs and skin grafts. In case of accidents and other health issues skin grafts may be required to enhance the health and well-being of a person. But an overly active immune response will make it impossible for the skin graft or the transplanted organ to become a normal part of the host. This is another issue that must be examined with regards to the regulation of T cell activity.

The presence of regulatory T cells should have been obvious but the truth is the study of Tregs is still at its infancy (Sakaguchi et al., p. 775). Yet in recent years the spotlight was focused on it when researchers first discovered an indirect link. The clue was first given when normal individuals with a significant proportion of cytotoxic T cells did not develop autoimmune disease or the extensive immune attack on normal tissues. This led to further research to determine the suppression action of some unknown agents. Research done in laboratories around the world made it possible to conclude that in fact there is a new class of T cells that help regulate the immune system. So that instead of attacking normal tissues and body organs it became more efficient in destroying external threats coming from harmful micro-organisms as well as in elimination of cancerous cells or tumours.

It all begins in the thymus. It is the part of the brain that produces T cells. The major function of Tregs can be summarized as the modulation of the immune response in a positive sense (Male, et al., p. 222). It is important to point out that Tregs does not prevent initial T cell activation. If it does then Tregs can be a harmful by-product of the body and must be eliminated. But the importance of Tregs can be seen in how it inhibits a “…sustained response and prevent chronic and potentially damaging immunopathology” (Male et al., p. 222). The means of suppression was further described to be a cell-to-cell contact type of mechanism (Prendergast & Jaffee, p. 283).

One of the key features of Tregs is that in contrast to naïve T cells they are completely and functionally mature while still within the thymus (Rose & Mackay, p. 120). It must also be added that it is naturally occurring (Male et al., p. 222). While it is already widely accepted that the thymus is a major site for the development of Tregs as well as the fact that it can be developed in the periphery there is still much to be desired when it comes to the exact mechanism that allows for the creation of Tregs as opposed to naïve T cells. The research team of Sakaguchi et al, made an important contribution when they pointed out the link between a transcriptor that could help explain the development of Tregs.

It has been suggested that the master regulator for Tregs is the fork-head box P3 (FOXP3). It is a transcription factor that is required for the development, maintenance and function of Tregs (Vignali, Collison, & Workman, p. 523). This was the conclusion made by many researchers when they discovered that in FOXP3 deficient mice Tregs are unable to develop (Rose & Mackay, 120). The FOXP3 is a member of the fork-head/winged-helix family of transcriptors (Sakaguchi et al., p. 776).

When the FOXP3 gene was found to be defective in laboratory mice, a problem called Scurfy was diagnosed. This problem was lethal in rodents as it promotes the hyperactivation of T cells as well as the overproduction of proinflammatory cytokines (Sakaguchi et al., p. 777). The same FOXP3 gene can be found in humans and its mutation was though to be the cause of a genetic disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), the human counterpart of Scurfy (Sakaguchi et al., p. 777). The similarities prompted many to link FOXP3 in Tregs development and function (Sakaguchi et al., p. 777). But there are those who argue that these results are far from conclusive.

There are those who asserted that although FOXP3 is needed for human T cell development, the expression of this gene is not enough to provide regulatory function (Vignali, Collison, & Workman, p. 523). This simply means that other components are needed so that Tregs can regulate the impact of T cells. This can also mean that the function of FOXP3 gene in humans is different from those of mice. While researchers are certain that FOXP3 plays a vital role in regulating T cell development, little is known when it comes to the specific mechanism in which FOXP3 instructs T cell development and function (Zhang, p. 9).

Aside from FOXP3 another important component needed by Tregs to function properly in suppressing the effects of T cells is a molecule known as Interlukin 2 (IL-2). In the laboratory mice lacking IL-2 developed fatal lymphoprolierative inflammatory disease with autoimmune components such as haemolytic anemia and lymphocytic infiltration (Sakaguchi et al., p. 777). This strengthens the view that aside from FOXP3 there are other components needed for the effective regulation of T cells.

Autoimmunity

There is a need to have an optimum balance when it comes to achieving immune homeostasis. In the laboratory, the absence of Tregs resulted in a T cell-mediated lymphoproliferative disease characterized by wasting and lymphocytic infiltration in multiple organs (Zhang, p. 6). In humans there are cytotoxic T cells that are scattered all over the body and it is only through the action of Tregs that the development of an autoimmune disease that is aggressive and ultimately fatal can be prevented (Weinberg, p. 668). One example of a serious autoimmune sickness is the inflammatory bowel disease (Blumberg & Neurath, p. 138).

The solution for autoimmune diseases can developed by using data obtained in study that that although the thymus may be the primary site for the development of FOXP3 Tregs there is also evidence that CD4⁺CD25⁺FOXP3 Tregs can develop from naïve peripheral CD4⁺CD25⁺ T cells (Rose & Mackay, p. 120). This means that it is possible to generate antigen-specific FOXP3 Tregs that in turn can be used in treating autoimmune and inflammatory diseases. This has prompted researchers to find a way to manipulate the presence of Tregs and T cells in the human body.

Cancer and Infectious Diseases

There is ample evidence to suggest that the human body can protect itself from all types of diseases as well as cancer (Weinberg, p. 669). This can be said of the human immune system which is a highly complex system able to eliminate threats coming from organic sources such as bacteria and other harmful micro-organisms. Yet, based on what has been discussed so far the human immune system must function at an optimum level and that the various components needed for it to work in perfect harmony with other organs of the body must be present or in perfect balance. On the other hand it can also be argued that an immune system that can ensure a cancer-free body may not be optimal because T cells in-charge of destroying harmful micro-organisms as well as the destruction of tumours and cancer cells can be present in excessive amounts making it susceptible to attacking normal human tissues.

Analysis

It has been made clear that the immune system must be regulated in order to increase its efficiency and the same time limit its deleterious effects. For the longest time knowledge regarding the complicated function of the mammalian immune system was limited to the proactive attributes of T cells. The enemy of the body are the foreign matter that comes in the form of micro-organisms. There are also undesired tissue developments that must be eliminated to sustain the functions of a healthy body. If the immune system failed to do these things then the body can be bogged down by infection as well as the effects of malfunctioning internal organs due to tumour and other cancerous growth.

A great deal of research has therefore been given to increase the effectiveness of the body’s immune system to make it even more invulnerable to microbial infections and from highly contagious diseases. Yet in recent decades there is another side of the immune system that generated much interest and it is the fact that it can turn against the host. The immune system must therefore maintain homeostasis in order to prevent this problem from occurring. Research must start from the root cause of the hyperactivation of the immune system and therefore making it impossible to achieve optimum tolerance.

The T cell that was highly praised for its significant contribution to the prevention of infections and other health problems can also be the problem if left unregulated. It should have been obvious – based on the relative success of the human race as the dominant species on the planet – that there must have been a regulator that is working hand-in-hand with T cells so that it its deleterious effect can be suppressed. But it was not until the middle of the 20^th century that this idea became grounded in facts. This is due in a large part to the work of Sakaguchi and his team of researchers at Kyoto University. Their work encouraged the scientific community to take a closer look at Tregs and how it specifically regulates the effect of T cell activity.

It must be pointed out that interest regarding Tregs can be traced to two major problems in the field of medicine. The first one is the age-old problem of finding ways to improve the capability of humans to ward of diseases and infections and the second is the need to solve problems related to organ transplants. With regards to strengthening the immune system from well-known diseases such as bacterial and viral infections there is also the need to prevent autoimmune diseases brought about by a malfunctioning immune system. On the other hand there is a need to look into the difficulty of achieving non-rejection of organ transplants.

By studying the intricacies of T cell activity as well as its counterpart the Tregs, researchers are hoping to hit two birds with one stone, so to speak. The review of related literature seems to suggest that scientists and medical experts are attempting to manipulate the presence of Tregs and T cells in the human body in order to achieve desired results. When it comes to preventing diseases the goal is to increase the activity of T cells for this is the one in-charge of attacking harmful micro-organisms and other pathogens. T cells are also needed to combat the growth of tumours and other unwanted cell growth in the body.

When it comes to preventing autoimmune diseases such as Type 1 diabetes and inflammatory bowel diseases the goal is to increase the capacity of Tregs to regulate the activity of T cells. This has been supported by research that induced the depletion of Tregs in mice. The result was the development of fatal autoimmune diseases where the immune system attacked normal tissues. In order to achieve these goals there are hurdles that must be overcome by researchers. This has to do with the need to have a complete understanding of how Tregs are created and how it is able to regulate the activity of T cells.

The first obvious hurdle is to determine the exact genes involved in the process of creating Tregs. The second hurdle is to find out the molecules that play a crucial part in the creation of Tregs. The third hurdle is the need to determine the exact mechanism in which Tregs suppress T cell activity. It was pointed out earlier that Tregs does not automatically inhibit the function of T cells but when in contact, it gradually affects T cell activity by limiting its capability for sustained action against normal tissues. In this regard there is also a need to find out the exact markers that will help researchers determine the exact components of Tregs as well as the other molecules that are needed to achieve tolerance.

Conclusion

Advances in medical science made it possible to understand what was once considered a mystery – the ability of human beings to thrive in a hostile world full of micro-organisms that can destroy the human body if given the chance to proliferate inside the individual. It is the inability of harmful viruses and bacteria to totally overwhelm mankind that gave him the chance to become the most dominant species on planet earth. But researchers discovered that man’s main weapon against infection and diseases can also be his weakness when it comes to achieving perfect health.

A hyperactive immune system is as deadly as highly contagious disease. The immune system can be deleterious to its host and instead of becoming its protector it can turn against it and damage healthy tissues and vital organs. The goal is to achieve homeostasis. This can be done by striking the correct balance between Tregs and T cell activities. A review of related literature suggests that there is an attempt to manipulate the Tregs and T cells to achieve specific results. For those who are suffering from cancer the reduction of Tregs will enhance the capability of T cells to eradicate tumours and other cancer-causing cells. For those who are suffering from autoimmune disease increasing Tregs is much preferred. The same is true for those who are unsuccessful in organ transplants and skin grafts.

Works Cited

Blumberg, Richard & Markus Neurath. Immune Mechanisms in Inflammatory Bowel Disease. New York: Spriner, 2006.
Male, David et al. Immunology. PA: Elsevier, 2006.
Prendergast, George & Elizabeth Jaffee. Cancer Immunotherapy. MA: Academic Press, 2007.
Rose, Noel & Ian Mackay. The Autoimmune Diseases. MA: Academic Press, 2006.
Sakaguchi, Shimon et al. “Regulatory T Cells and Immune Tolerance.” Cell 10.1016 (2008): 775-786.
Taams, L.S. & A.N. Akbar. “Peripheral Generation and Function of CD4⁺ CD25⁺ Regulatory T Cells.” CD4⁺ CD25⁺ Regulatory T Cells. Ed. Bruno Kyewski & Elizabeth Suri-Payer. New York: Springer, 2005. 115-125.
Vignali, Dario, Lauren Collison, & Creg Workman. “How Regulatory T Cells Work.” Immunology 8 (2008): 523-532.
Weinberg, Robert. The Biology of Cancer. New York: Garland Science, Taylor & Francis Group, 2007.
Zhang, Jingwu. Immune Regulation and Immunotherapy in Autoimmune Disease. New York: Springer, 2007.

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