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Different sub-classes of a type of white blood cell involved in autoimmune diseases such as multiple sclerosis (MS) arise independently within the immune system, according to a finding from St. Jude scientists that provides new insight into how autoimmunity is controlled.
The work answers a key question about the origin of two types of immune cells, known as regulatory and effector T lymphocytes. These play very different roles in the immune system and in a disease in mice that mimics MS in humans. Effector T cells promote disease whereas regulatory T cells protect against the misguided immune system attack that characterizes autoimmune disorders such as MS. The research is published in the December 18 issue of the journal Immunity.
The investigators demonstrated that regulatory and effector T cells isolated from the central nervous system of mice with the MS-like disease both recognize and respond to the same antigen. An antigen is a protein or other substance that triggers an immune response. The different types of T cells engage the antigen in the same way and with similar binding strength. But researchers reported that the T cell types, despite targeting the same antigen, arose from different populations of lymphocytes.
Regulatory T cells are important in controlling immune responses and safeguarding healthy tissue. They can be identified by their unique expression of a protein called Foxp3, which is a type of protein called a transcription factor. Foxp3 can alter the expression of many different genes that give regulatory T cells the ability to modulate immune responses.
In MS, the immune system targets the myelin sheath that insulates and protects nerve fibers. T cells linked to the disease, called effector T cells, recognize antigens present within this myelin sheath and initiate its destruction. An estimated 400,000 Americans have the disease. In the Immunity study, scientists used mice that developed a similar disease. In both mice and people, regulatory T cells are believed to be important in controlling the disease.
Earlier research suggested a more flexible T cell response was possible in autoimmune disorders, including evidence that effector T cells could be induced to express Foxp3 and function like other regulatory T cells in a process known as interconversion. These new findings suggest if this occurs, it is infrequent at least in some autoimmune diseases.
To study the origins of the T cell populations, the researchers focused on the receptors carried on the surface of T cells. Those highly diverse receptors determine the antigen a T cell recognizes and responds to. Millions of possible T cell receptors can be expressed by different T cells. Analyzing the differences between receptors expressed by regulatory versus effector T cells at sites of disease and in other locations helped illuminate the relationship between these populations of cells. Based on the analysis, researchers concluded there was little interconversion between the regulatory and effector populations.
“This work gives us insight into the fundamental nature of the T cell response during autoimmunity and the different T cell receptors that are guiding the pathologic effector and protective regulatory T cells. It is important to consider the distinct origins and limited plasticity of the cells when designing therapeutic manipulations to enhance one population of T cells versus the other,” said Terrence Geiger, MD, PhD, Pathology, and the study’s senior author. “This is really basic research, but there are clinical implications.”
Although scientists recognized several years ago that regulatory T cells were important in moderating the immune response, the origin of those regulatory T cells in disease states was less clear, Geiger said. In contrast to the disease setting, in laboratory cultures, effector T cells can be induced to produce Foxp3 and act like regulatory T cells.
Geiger said such conversion might be more common in other autoimmune diseases, particularly inflammatory bowel disease. “Cells capable of promoting up-regulation of Foxp3 seem to be particularly prominent in the gut,” Geiger said. Xin Liu, MD, the study’s lead author, said there was no evidence interconversion played an important role in mice with this model of MS. Liu is a graduate student in Geiger’s laboratory and the University of Tennessee Health Sciences Center.
For this study, Liu developed a new animal model that allowed investigators to use the sequences of T cell receptors as bar codes to track the origins of both regulatory and effector T cells. The cells were taken from the spleen and central nervous system of healthy and diseased mice. While the spleen servers as a reservoir of T cells, the central nervous system is targeted in this disease. The T cell receptor genes expressed by these cells were isolated and sequenced.
The approach generated sequences of thousands of different receptors for analysis. The researchers also took 40 of the receptor genes commonly identified in either spleen or central nervous system T cells and inserted them into T cells that lacked their own receptors. This enabled investigators to study which antigen the individual receptors recognized as well as how the receptor recognized its antigen. The scientists determined that recognition of antigens by regulatory and effector T cells was similar. Investigators also reported about half of the receptors recognized a myelin antigen. Researchers analyzed the sequences of the receptors and identified specific subunits called amino acids that appeared important for either myelin recognition or for differentiation into regulatory T cells.
Other authors of this paper include Phuong Nguyen, Pathology; Wei Liu and Cheng Cheng, PhD, both of Biostatistics; John Obenauer and Jing Ma, both of Information Sciences; and Meredith Steeves, formerly of St. Jude.
This study was supported by the National Institutes of Health and ALSAC.