Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production through a negative feedback regulation loop.

摘要

IL-2 is essential for T cell expansion and effector cell development in vitro and for the generation and maintenance of Treg cells in vivo. In our attempts to identify differentially expressed molecules dependent on IL-2 in activated T cells, DNA microarray analysis identified Blimp-1 as one such target. Blimp-1 is minimally expressed in naive T cells but highly induced in activated T cells. Time-course experiments indicate that Blimp-1 is induced between 24 and 48 hr after stimulation through TCR and costimulatory molecules. Blimp-1 expression mainly depends on IL-2, as T blasts cultured with anti-IL-2 and activated T cells with defective IL-2Rbeta signaling did not express Blimp-1. This cytokine dependency for Blimp-1 expression is not restricted to IL-2, because exogenous IL-4 or IL-12 also induces Blimp-1, even though to a less extent.; For activated T cells that expressed less IL-2, Blimp-1 expression was higher, correlating Blimp-1 with the inability to properly produce IL-2. Activated T cells that were transduced with Blimp-1 produced less IL-2 and inhibited an IL-2 reporter construct consisting of 8.4-kb 5'-upstream DNA sequence of the IL-2 gene, while granzyme B and CD25 expression were somewhat enhanced. These findings indicate that IL-2 inhibits its own production through a Blimp-1-dependent negative feedback regulation loop while promoting a T effector cell phenotype.; Of the three major pathways downstream of IL-2, both Stat5 and PI3K, not MAPK, contribute to Blimp-1 induction and IL-2 down-regulation, since ectopic expression of constitutively-active Stat5 enhanced Blimp-1 expression while down regulating IL-2 whereas PI3K inhibitor, not MAPK inhibitor, abolished Blimp-1 expression while increasing IL-2 production. However, Stat5 itself is not sufficient to induce Blimp-1 or down-regulate IL-2 in activated T cells with defective IL-2Rbeta, suggesting that other factors are needed for Stat5 to induce Blimp-1 and subsequently inhibit IL-2.; Our discovery that IL-2 controls its own production through a Blimp-1-dependent negative feedback regulation loop helps explain the transient nature of IL-2 production during immune responses. Moreover, as Blimp-1-deficient T cells in vivo exhibit dysregulated T cell homeostasis and autoimmunity, our findings also raise the possibility that improper regulation of IL-2 production may contribute to these pathological abnormalities.