Scientists Identify A New Molecular Brake That Can Curb Excessive Immune Activation

Main Category: Immune System / Vaccines
Article Date: 16 Jul 2008 - 4:00 PDT

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In new research published in the open access, peer-reviewed online journal PLoS ONE, a team of scientists from NYU School of Medicine report the identification of a molecule expressed on a special class of T cells called regulatory T cells that appears to play a role in allowing these cells to control immune responses.

The researchers speculate that identification of this novel molecule as a modulator on regulatory T cells may help pave the way for new approaches to suppress immune responses as a means to treat autoimmune diseases, chronic inflammation during infections such as HIV, or for preventing transplantation rejection.

The immune system is a highly organized and intricate network consisting of nearly a dozen cell types whose primary function is to protect the body from infectious organisms. To perform this function, cells of the immune system are armed with powerful molecular "weapons" that can kill or neutralize pathogens. However, as important is a potent immune response in ridding the body of invasive pathogens, it can also be a double-edged sword if not properly controlled, with the potential for prolonged inflammatory responses to cause extensive damage to "innocent bystander" host cells.

Two extensively studied cell types of the immune system, T and B cells, naturally undergo a selection process during their development that is intended to eliminate any cells that recognize self-antigens. Such cells could otherwise have the potential to initiate autoimmune responses, which are defined as immune cell attacks against normal host tissues. The fact that autoimmune diseases are prevalent is thought to reflect inherent imperfections in this selection process, with some auto-reactive T and B cells managing to escape elimination.

Because immune responses have the potential to be harmful, there are several built-in safety mechanisms that constantly regulate, with exquisite sensitivity, the degree of response. A major mechanism that ensures control of immune responses is mediated by a professional T cell subset called regulatory T cells or Tregs. These cells are specialized in suppressing the activation of other immune system cells, especially T cells, thereby helping maintain a state of tolerance to self-antigens.

Based on studies in humans as well as mice, genetic defects in Treg cells have been shown to lead to massive autoimmune diseases and death due to uncontrolled immune activation. Although several mechanisms have been proposed, it still remains unclear how Tregs mediate their suppressive function.

Now a team led by Dr. Derya Unutmaz at the New York University School of Medicine has identified a molecule that is expressed on Tregs and could mediate part of their potent suppression of immune reactions. The molecule, which is called GARP (or LRRC32), was previously detected in other tissues including blood platelets, but no function for the protein that it encodes had been defined.

Dr. Unutmaz's lab, using microarray analysis, found that GARP was one of the few molecules highly expressed on activated Tregs compared to other T cell subsets. They then genetically engineered conventional T cells to express GARP and showed that these cells acquired partial characteristics of suppression. In a reverse experiment, Dr. Unutmaz and colleagues knocked down expression of GARP in genetically reprogrammed human Tregs, which resulted in a corresponding reduction in their capacity to inhibit T-cell activation.

If GARP is also shown to be an important regulator of immune response in vivo, as suggested by cell culture experiments, it can be potentially developed as a treatment approach against autoimmune diseases or to prevent transplantation rejection. This can be potentially achieved by enhancing the expression of GARP in either Tregs or different cell types such as transplant tissue. Alternatively, biological or small molecules as drugs with the capability to mimic GARP signals may also be developed as therapeutics.

While Tregs are critical in controlling harmful immune reactions, there are possible scenarios in which over-regulation by these cells may lead to insufficient response to pathogens or ineffective vaccination. It is also conceivable that some tumor cells express GARP to elude the immune system. Thus, in such cases blocking the function of GARP could potentially amplify immune responses to infectious diseases or cancers.

Dr. Unutmaz and colleagues are particularly excited that discovery of this molecule as a novel immune suppressor enhances the toolbox available to scientists to both explore and modulate the delicate balance of immune system function.

Graduate student Rui Wang in Unutmaz lab was the lead author in the characterization of GARP function. Additional authors who contributed to this study were Qi Wan, Lina Kozhaya and Hodaka Fujii.

Funding: This study was supported by funding from National Institutes of Health, National Institute of Allergy and Infectious Diseases grant R01 AI065303 to Derya Unutmaz.

Identification of a Regulatory T Cell Specific Cell Surface Molecule that Mediates Suppressive Signals and Induces Foxp3 Expression.
Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D (2008)
PLoS ONE 3(7): e2705. doi:10.1371/journal.pone.0002705
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