Despite the crucial roles of GATA-3 in lymphocyte biology, little is known about its intracellular distribution and the mechanisms regulating its nuclear import. Single-cell analyses on confocal microscopy images revealed that GATA-3 was enriched in the nucleus of naive and T helper (Th)2 cells, whereas Th1 cells preferentially accumulated it in the cytoplasm. This GATA-3 compartmentalization was mirrored in innate lymphoid cells ex vivo. In vitro or in vivo reprogramming of Th1 and Th2 cells reversed the subset-specific GATA-3 localization and triggered the acquisition or loss of GATA-3-dependent effector functions, respectively. We identified importin-β as the transporter mediating GATA-3's nuclear import. In Th2 cells, the subtle cytoplasmic accumulation of GATA-3 following importin-β blockade disrupted the GATA-3 autoactivation loop and impeded type 2 cell features. This sensitivity was explained by the prompt nuclear degradation of GATA-3, thus emphasizing that Th2 cell function depends on continuous and maximal nuclear import of GATA-3. Our results highlight the control of GATA-3 import into the nucleus as a fundamental rheostat of lymphocyte biology.
Saikali et al. (Sun,) studied this question.