The Transcription Factor NFAT Exhibits Signal Memory during Serial T Cell Interactions with Antigen-Presenting Cells

Abstract

Summary Interactions with antigen-presenting cells (APCs) interrupt T cell migration through tissues and trigger signaling pathways that converge on the activation of transcriptional regulators, including NFAT, which control T cell function and differentiation. Both stable and unstable modes of cognate T cell-APC interactions have been observed in vivo, but the functional significance of unstable, serial contacts has remained unclear. Here we used multiphoton intravital microscopy in lymph nodes and tumors to show that while NFAT nuclear import was fast (t1/2 max~1min), nuclear export was slow (t1/2~20min) in T cells. During delayed export, nuclear NFAT constituted a short-term imprint of transient TCR signals and remained transcriptionally active for the T cell tolerance gene Egr2, but not for the effector gene Ifng, which required continuous TCR triggering for expression. This provides a potential mechanistic basis for the observation that a predominance of unstable APC interactions correlates with the induction of T cell tolerance.

T cell activation requires force generation

“…TCR signaling that was abbreviated induced anergy caused by nuclear factor of activated T cells (NFAT)-driven transcription (Marangoni et al, 2013). Cyclic adhesion of single-molecule pMHCs to T cells using a biomembrane force probe showed that 5-s intervals between contacts were sufficient to produce Ca 2+ flux, whereas 10 s was insufficient (Pryshchep et al, 2014).…”

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

“…Our findings have reminiscence of the initial characterization, by multiphoton imaging, of phases of T cell motility during lymph node priming (17, 18), which has fueled ongoing works to under-stand cell-cell interactions and the biology of T cells during each phase. We do note that the apparent lack of antigen recognition may mask weak antigen recognition, as multiple studies have documented "motile synapses" that are effective in some elements of signaling in vivo (42)(43)(44). That these late-phase interactions are likely antigen independent is supported by the apparent lack of a role for either TCR stimuli (e.g., ZAP70) or the appearance of TCR-induced signals (e.g., NUR77), although signals might be generated but are just too weak for these methods to detect.…”

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

“…To correlate calcium changes with the activation events downstream of calcium signaling, we followed the calcium-dependent nuclear translocation of a truncated Nuclear Factor of Activated T Cells (NFAT)-GFP fusion protein (8,14,15).…”