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    New clue to machinery of autoimmune disease

    Terrence L. Geiger, MD, PhD

    St. Jude researchers have discovered an intriguing insight into how T cells, the immune system’s master regulatory cells, wage war on the body’s own tissues in such autoimmune disorders as multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Their findings about T cells add another piece to the puzzle of understanding such diseases. While the findings are quite basic, they could contribute to designing therapies to suppress the immune responses that are misdirected against a person’s own tissues in autoimmune disorders.

    T cells launch the immune system into action when they encounter bits of foreign protein, called antigens. T cells sense these antigens—which may come from invading viruses or bacteria—through receptors on the T cells’ surface. These receptors recognize and attach to specific antigens like a key fitting a lock. Many autoimmune diseases arise when T cell receptors that recognize the body’s own proteins, called “self” antigens, spur T cells to mistakenly launch an immune system to attack body tissues.

    “T cells have potentially millions of different possible receptors,” said Terrence Geiger, MD, PhD, Pathology, the senior author of a report on this work that appears in the July 1 issue of the Journal of Immunology. “Some T cell receptors are adept at promoting autoimmunity, some are poor and some are protective. It is not clear why one T cell receptor can promote autoimmunity, whereas another T cell receptor on a similar kind of T cell either doesn’t do anything, or even protects against autoimmune reaction.”

    Geiger and his colleagues began their study with the hypothesis that T cell receptors that trigger autoimmunity might be those that latch more tightly onto, or have a greater affinity for, a self antigen. To test this possibility, they engineered mice to express either of five slightly different T cell receptors, all of which recognize a piece of a protein from the central nervous system, called MOG. T-cells are directed against MOG in patients with multiple sclerosis (MS) or mice with a MS-like disease. To insert the receptors into the mouse T cells, the researchers used a technique called “retrogenic modeling” that was perfected by the laboratory of Dario Vignali, PhD, Immunology. In this technique, a harmless virus is used as a carrier to insert specific T cell receptors into bone marrow cells that then mature into T cells.

    The researchers’ measurements established that each different T cell receptor had a different affinity for the MOG protein. They then tested whether the mice with receptors that grabbed more tightly onto MOG developed more severe autoimmune disease than those that bound more loosely.

    Young mice expressing each of the different receptors on their T cells did not differ in their development of the multiple sclerosis-like disease when they were immunized with the MOG protein. However, as the mice aged, they did spontaneously develop disease. The mice expressing the different receptors differed significantly in their susceptibility to this spontaneous autoimmunity. Curiously, receptor affinity did not appear to affect disease susceptibility or severity. Instead, the researchers found that mice that were more likely to spontaneously develop autoimmune disease were those that, for some reason, had produced a greater number of T cells with the MOG receptor—that is, they had a higher level of “engraftment.” Indeed, the researchers were able to associate the number of T cells measured in a mouse’s blood with the likelihood of that mouse developing disease months later.

    “This finding of an association between T cell engraftment and spontaneous disease suggested to us that there is some barrier to the development of disease,” Geiger said. “Why are cells that engraft better more likely to cause disease? We really don’t know the answer. Once the mice start to get disease, they get very sick, but there is sort of a triggering point. Our findings may suggest that disease triggering in these models involves a mass effect that requires some quantity of specific T cells to ignite disease. But we really want to find out whether it is the cell number itself or whether receptor recognition properties that lead to increased engraftment also lead to increased susceptibility to disease. These are things we can test.”

    “These findings don’t have a direct clinical implication right now, but if we understand which T cells induce pathology and why, and which cells are protective or passive, we will gain a better sense of where to target what are called antigen-specific therapies,” Geiger said. “Those therapies try to selectively target the T cells that cause disease, sparing the rest of the immune system.”

    Other authors of this study include Rajshekhar Alli, PhD, and Phuong Nguyen, both of Pathology.

    This work was supported by the National Institutes of Health and ALSAC.

    August 2008