SUMMARY | FULL STORY
IMMUNOLOGY
Target Found for Boosting T Cell Tolerance, 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 present in T cells 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 factor, NFAT, pairs with another transcription factor, AP-1, and brings about a full-blown immune response in which T cells fight foreign antigens. If NFAT does not pair with AP-1, however, it brings about a state of T cell unresponsiveness in which the T cells tolerate antigens. A full immune response to a transplanted organ's foreign antigens is the cause of organ rejection. So if drugs could be designed to prevent the interaction of NFAT and AP-1, this destructive response might be prevented and tolerance induced. Currently, the immunosuppressive drug cyclosporin is used by transplant patients to prevent rejection by shutting down the activity of NFAT. But in doing so, the drug also stops NFAT's initiation of T cell tolerance.
Tolerance is brought about through a process of incomplete signaling. The body's own antigens--self-antigens--stimulate only the T cell receptor, causing an increase in intracellular calcium levels that activates NFAT. The NFAT then binds to specific sites of the T cell DNA, triggering expression of genes that induce a tolerant state.
Rao's team found that in cells stimulated by foreign antigens, the T cell receptor as well as another, costimulatory receptor, are activated. The NFAT then binds with AP-1 on a different site of the DNA and turns on genes that help fight the antigens. "Pathogens override incomplete signaling to self-antigens and trigger a full-blown immune response to infection," Rao said.
The researchers now plan to design compounds that would prevent the interaction of NFAT and AP-1 as the foundation of an improved approach to treating transplant patients.
--Sena Desai
Copyright 2002 by the President and Fellows of Harvard College
