Tolerance

T-cell turn-off

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

  1. 1

    Macián, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002) | Article |

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Bell, J. T-cell turn-off. Nat Rev Immunol 2, 460 (2002). https://doi.org/10.1038/nri863

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