Stat3 Phosphorylation Mediates Resistance of Primary Human T Cells to Regulatory T Cell Suppression

Abstract

Human autoimmune diseases are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells that are inadequately suppressed by regulatory T cells (Tregs). IL-6, which is overexpressed in tissue and serum of patients with autoimmune diseases, inhibits human Treg function. We sought to determine the mechanism for the antitolerogenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. Inhibition of Stat3 signaling in MLCs containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6–mediated loss of Treg suppression requires phosphorylation of Stat3. Cultures in which either effector T cells (Teffs) or Tregs were pretreated with Stat3 inhibitors indicate that phosphorylated (p)Stat3 is required in both T cell populations for IL-6–mediated reversal of Treg function. IL-21, which signals preferentially through pStat3, also reverses Treg suppression, in contrast to IL-27 and IFN-γ, which signal preferentially through Stat1 and do not inhibit Treg function. Interestingly, both Teffs and Tregs respond to IL-6 stimulation through strong Stat3 phosphorylation with minimal MAPK/Erk activation and moderate Stat1 phosphorylation. Finally, Teffs stimulated strongly through the TCR are also resistant to suppression by Tregs and show concurrent Stat3 phosphorylation. In these cultures, inhibition of pStat3 restores functional suppression by Tregs. Taken together, our findings suggest that an early dominance of Stat3 signaling, prior to subsequent T cell activation, is required for the loss of functional Treg suppression and that kinase-specific inhibitors may hold therapeutic promise in the treatment of autoimmune and chronic inflammatory diseases.

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

“…Specifically, Goodman and colleagues demonstrated that inhibition of STAT-3 restores immunosuppressive function by T regs stimulated previously with IL-6 [47]. Our results are consistent with this notion, and imply that increased STAT-3 phosphorylation in T regs is the hallmark of resistance to suppression in SLE.…”

“…However, the role of ubiquitination in resistance to suppression phenotype in SLE has not been defined completely. Although many studies have suggested that resistance to suppression in SLE is due to an effector T cell resistance and not to an abnormal regulatory function [15,16], it has been demonstrated that this subpopulation displays some molecular defects which could be associated with the acquisition of an effector phenotype [46,47].…”

“…Previous studies have proposed that resistance to suppression by T regs is dependent upon the STAT-3 signalling pathway, as inhibition of this molecule reverts the resistance to suppression phenotype by T regs stimulated previously with IL-6 [47]. Moreover, the role of different ligases, such as tumour necrosis factor-associated factor 6 (TRAF-6), in the ubiquitination of STAT-3 to promote degradation has been well demonstrated [48].…”

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

“…We can offer two possible explanations: first, Ag dose has been shown to be an important determinant for Treg differentiation in which high Ag doses favor the induction of effector T cells, whereas low Ag doses lead to increased Treg differentiation (43). Second, it has been shown that the inflammatory environment, in particular the levels of the proinflammatory cytokine IL-6, critically influence the balance of Treg versus T effector differentiation (44,45). Interestingly, DC-T cell interaction in the presence of high Ag doses favors the production of IL-6 and hence the suppression of Treg induction (43).…”

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

“…Resistance to Treg-mediated suppression has previously been associated with activation of STAT3 in responder T cells (48). We therefore measured STAT3 phosphorylation in CD161 + and CD161…”