Activation-Induced Inhibition of Interleukin 6–Mediated T Cell Survival and Signal Transducer and Activator of Transcription 1 Signaling

Abstract

The cytokines interleukin (IL)-2, IL-4, IL-6, IL-7, and IL-15 have all previously been shown to inhibit resting T cell death in vitro. We have found a difference in the response of T cells to IL-6, depending on the activation status of the cells. IL-6 inhibited the death of naive T cells, but had no effect on the death of either superantigen-activated T cells, or T cells bearing memory markers. This was true even when the resting and activated T cells were isolated from the same animal; thus, the determining factor for IL-6 insensitivity was the activation status or activation history of the cell, and not the milieu in the animal from which the cells were isolated. Activated T cells expressed lower levels of IL-6 receptors on their surfaces, yet there were sufficient levels of receptors for signaling, as we observed similar levels of signal transducer and activator of transcription (Stat)3 phosphorylation in resting and activated T cells treated with IL-6. However, there was profound inhibition of IL-6–induced Stat1 phosphorylation in activated T cells compared with resting T cells. These data suggest that there is activation-induced inhibition of IL-6 receptor signaling in T cells. This inhibition appears to be specific for some but not all of the IL-6–mediated signaling cascades in these cells.

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

“…IL-6 can also promote T cell survival (35,36), raising the possibility that limiting amounts of IL-6 might contribute to the arrested phenotype. Addition of IL-6 to naive T cells induced to proliferate in the absence of IL-4, IFN-␥, and IL-12, however, was unable to overcome these cytokine-dependent requirements for full activation ( Fig.…”

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

“…T lymphocytes can be protected from SFD-induced apoptosis by members of the common ␥-chain cytokine family, including IL-2, IL-4, IL-7, IL-9, and IL-15 (17), and type I IFNs (18). IL-6 has also been shown to protect T cells from SFD-induced apoptosis (19,20). Intriguingly, this may operate through two distinct mechanisms.…”

CD40 Induces Interleukin-6 Gene Transcription in Dendritic Cells

“…A direct effect of IL-6 on the proliferation of T cells has been documented by several groups (3)(4)(5)(6)(7)(8), as has the ability of IL-6 to prevent the death of naive T cells (9). Other studies have described the ability of IL-6 to induce IFN␥ secretion in differentiating T cells; indeed lack of this response in IL-6 gene knockout mice renders animals unable to mount T cell responses against Mycobacterium.…”

“…IL-6 is a highly pleiotropic cytokine with properties that indicate it is not only a stimulator of the activation, proliferation, and survival of T cells (3)(4)(5)(6)(7)(8)(9), but is also able to modify DC function and survival (1,10,11). A direct effect of IL-6 on the proliferation of T cells has been documented by several groups (3)(4)(5)(6)(7)(8), as has the ability of IL-6 to prevent the death of naive T cells (9).…”