A study that is published in Cell this month shows that NFAT (nuclear factor of activated T cells) — a transcription factor that has a central role in full T-cell activation — can also initiate a genetic programme that leads to anergy.
Anergy is a state of lymphocyte non-responsiveness that is induced by suboptimal antigen stimulation, and it is thought to be important in preventing harmful responses to self-antigens. But, the biochemical pathways that lead to anergy rather than full activation are poorly understood.
Macián and co-workers investigated whether the Ca2+ signalling pathway triggers a distinct genetic programme that leads to anergy. They used an in vitro model in which CD4+ T cells are treated with ionomycin — an activator of the Ca2+–calcineurin–NFAT signalling pathway — to mimic signalling through the T-cell receptor (TCR) only and induce anergy, or with PMA (phorbol 12-myristate 13-acetate) and ionomycin to mimic full activation by TCR signalling and co-stimulation. Microarray analysis of global gene expression showed reproducibly that the expression of ∼70 genes was induced more strongly (or as strongly) by ionomycin alone than by PMA and ionomycin.
The ability of NFAT to regulate the expression of these anergy-associated genes was then assessed. NFAT1 is the predominant member of the NFAT family in T cells, and in ionomycin-treated Nfat1−/− T cells, the expression of 15 out of 18 anergy-associated genes tested was reduced compared with wild-type T cells. Nfat1−/− T cells were less susceptible to the induction of anergy, which further indicates a role for NFAT in this process.
Interaction of NFAT with the nuclear factor AP1 is essential for the transcription of effector cytokine genes during T-cell activation, but is this interaction involved in the induction of anergy? Activation of AP1 was not detected in ionomycin-treated T cells. Furthermore, the transduction of T cells with a constitutively active NFAT1 that cannot interact with AP1 was sufficient to render the T cells anergic and to induce the expression of several anergy-associated genes.
On the basis of their results, the authors propose a new model of T-cell anergy (see figure). Importantly, this model predicts that blockade of the NFAT–AP1 interaction should prevent T-cell activation and induce a long-lasting state of tolerance. This is a key goal of organ transplantation that current regimes of immunosuppression fail to achieve.
ORIGINAL RESEARCH PAPER
Macián, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002) | Article |
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Proceedings of the National Academy of Sciences (2020)