IMNMUNOLOGY Tolerance from NFAT

Signals from the T cell receptor cause T cell activation if signaling also occurs through costimulatory receptors. But activation of the T cell receptor alone causes the cells to become unresponsive or anergic, producing immune tolerance. Macián et al. report that, in fact, activation of the same transcription factor--NFAT (nuclear factor of activated T cells)--is critical for signaling both activation and tolerance. NFAT is well known to participate in calcium-dependent gene expression in activated T cells. The authors used transcriptional arrays to identify a set of genes whose expression was increased in anergic cells. Mouse T cells lacking NFAT were resistant to induction of anergy in vitro and showed reduced expresssion of genes normally expressed in response to anergic signals. To cause a productive immune response, NFAT interacts with another transcription factor, AP-1. But expression of constitutively active NFAT induced anergy even if the protein was modified to disrupt interaction with AP-1 complexes. The authors point out that the NFAT-AP1 interface might be a useful target for agents designed to suppress immune response as required, for example, in transplant patients.

F. Macián, F. García-Cózar, S.-H. Im, H. F. Horton, M. C. Byrne, A. Rao, Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719-731 (2002). [Online Journal]