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IMMUNOLOGYMolecular Target Found for Boosting T Cell ToleranceBlocking Transcription Factor Pair May Be Boon to Organ Transplantation A team of researchers led by Anjana Rao, HMS professor of pathology at the Center for Blood Research, has found that a transcription factor, NFAT, mediates two completely opposing immune responses.
Fernando Macián, Anjana Rao, and Sin-Hyeog Im (l to r) have revealed that NFAT mediates two opposing biological programs. They hope their findings will help in developing therapies to prevent rejection of transplanted organs. (Photo by Graham Ramsay) "The immune system is balanced on a tightrope," said Rao. And research by lab members Fernando Macián, Francisco García-Cózar, and Sin-Hyeog Im suggests that it is NFAT (nuclear factor of activated T cells) that performs this balancing act. When NFAT pairs with another transcription factor, AP-1, it helps T cells fight foreign antigens; if it does not bind with AP-1, it induces anergy in the T cells, a state in which they tolerate antigens. The investigators plan to explore how to take advantage of this mechanism, which they report in the June 14 Cell, to prevent rejection of transplanted organs. If a drug could be designed to prevent the interaction of NFAT and AP-1, it might be used to stimulate in transplant patients long-term tolerance of the new organs. Such a drug might also be useful in treating autoimmune diseases by making patients tolerant to the self-antigens their immune systems are reacting with. Mark of TolerancePrevious research had shown that there is an increased level of intracellular calcium in cells that are tolerant of self-antigens. To see how the increase induces tolerance, the researchers treated T cells in a culture dish with ionomycin, a compound that increases intracellular calcium. DNA microarray analysis, performed in collaboration with Michael Byrne and Heidi Horton at Wyeth Research in Cambridge, showed that higher levels of intracellular calcium caused the expression of a specific pattern of genes that were different from those transcribed in response to full immune stimulation. Remarkably, the same genes were also expressed in T cells made tolerant to a foreign antigen by feeding the antigen to mice.Rao's earlier research had shown that calcium activates NFAT. To see if the transcription factor had a role in inducing T cell tolerance, the researchers did experiments on T cells that lacked NFAT1, the predominant NFAT family member in resting T cells. These cells were more resistant to developing tolerance and showed decreased expression of the anergy-associated genes. Self-antigens stimulate only the T cell receptor, causing increased intracellular calcium that, in turn, activates NFAT. NFAT proteins then bind to specific sites on the DNA, triggering the distinct pattern of gene expression peculiar to tolerant T cells. On the other hand, the presence of pathogens and other foreign antigens induces proteins that activate costimulatory receptors on the T cell surface. Combined stimulation of the T cell receptor and costimulatory receptors induces activation of Fos and Jun proteins, which make up the transcription factor AP-1. Under these conditions, NFAT interacts with AP-1 on different DNA sites, causing expression of a completely different set of genes that help fight the pathogen. To demonstrate this process, the researchers transduced T cells with an NFAT protein that is active but unable to interact with AP-1. These T cells turned on several anergy-associated genes and became unresponsive. In contrast, an active NFAT that did interact with AP-1 was able to turn on genes associated with a normal immune response. "Pathogens override incomplete signaling to self-antigens and trigger a full-blown immune response to infection," Rao said. "Of the 30,000 or more genes in the genome, about a thousand genes are turned on in T cells during a complete immune response to a foreign antigen, but only about a hundred seem to be turned on in response to self-antigens." Blocking Graft Rejection"This study may help define and develop therapies for organ transplants," said Macián, an HMS research fellow at the CBR and one of the lead authors of the study. The foreign antigens associated with transplanted organs induce a productive immune response in the body, causing organ rejection. So far, two different approaches to prevent rejection have been used. The immunosuppressive drug cyclosporin is used to prevent graft rejection by inhibiting calcineurin, an enzyme that dephosphorylates and activates NFAT. Blocking costimulatory receptors has also been used to induce tolerance to transplanted organs. However, neither of these therapies has proven completely successful and, when combined, they interfere with each other. This may be because cyclosporin inhibits NFAT activation, thereby also blocking induction of tolerance in T cells."Ideally, interference with NFAT and AP-1 interaction would immunosuppress and, at the same time, induce a long-lasting state of tolerance," said Macián. The approach would be preferable to inhibiting NFAT activation altogether with cyclosporin. If used in combination with costimulatory blockade, it might avoid problems associated with other therapies and prove a more successful approach to treating transplant patients and autoimmune diseases. The researchers now plan to design compounds that would prevent the interaction of NFAT and AP-1. --Sena Desai |
