Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Abstract

Transcription factor retinoid acid-related orphan receptor gamma t (RORγt) transcriptionally regulates the genes required for differentiation of T helper 17 (Th17) cells that mediate both protective and pathogenic immunity. However, little is known about the function of post-translational modifications in the regulation of RORγt activity. Mass spectrometric analysis of immunoprecipitated RORγt from Th17 cells identified multiple phosphorylation sites. Systematic mutation analysis of the identified phosphorylation sites find that phosphorylation of serine 376 (S376) enhances whereas phosphorylation of serine 484 (S484) inhibits Th17 differentiation. IKKα binds and phosphorylates RORγt at S376 but not S484. Knockdown of IKKα, dominant negative IKKα and RORγt mutants incapable of interacting with IKKα all decrease Th17 differentiation. Furthermore, nonphosophorylatable RORγt mutant (S376A) impairs whereas phosphomimetic mutant (S376E) stimulates Th17 differentiation independent of IKKα. Therefore, IKKα-dependent phosphorylation of S376 stimulated whereas IKKα-independent phosphorylation of S484 inhibited RORγt function in Th17 differentiation.

T‐lymphocyte–specific knockout of IKK‐2 or NEMO induces T h 17 cells in an experimental nephrotoxic nephritis mouse model

“…However, an anti-inflammatory role for IKK-2 through the inhibition of canonical pathway activation has also been described (18,44). The post-translational phosphorylation of IKK1 is responsible for both positive and negative regulation of retinoic-acid-receptor-related orphan nuclear receptor-gt activity in T h 17 differentiation as shown by He et al (45). Our array data also demonstrate that T h 17-related cytokines were up-regulated in CD4 + T cells from CD4xNEMO D mice.…”

Resolvin E1 Regulates Th17 Function and T Cell Activation

“…We tested the hypothesis that the RvE1 will restore homeostatic balance and inflammation by targeting the T h 17 activation, a critical step in the chronicity of inflammation. We used the splenocyte-derived CD4 + T cells and CD11c + DCs (41)(42)(43)(44)(45) and minimized inter-individual variations. We applied the RvE1 at baseline and day 3 since supplementary doses were necessary to show its impact.…”

“…Receptor-mediated production of cytokines is critical for T h 17 function. RORgt receptor expression is necessary for effector T h 17 cells and an efficient cytokine production such as IL-17 (23)(24)(25)(44)(45)(46)(47)(48). In addition to the IL-17, IL-21 is generated by T cells in the A B FIGURE 7 | (A) shows representative flow cytometric data (above) and proportion (below) of FoXP3 + cells in CD4 + gate in T cells+ DCs, T cells+DCs+RvE1, T cells+ DCs+ PAM 3 CSK 4 and T cells+ DCs+ PAM 3 CSK 4 + RvE1.…”

Gastric Juice Expression of Th-17 and T-Reg Related Cytokines in Scleroderma Esophageal Involvement

“…In our patients, we found that gastric juice levels of IL-10 and TGF-β, the two most representative T-reg cytokines, were lower in patients with esophageal dysmotility. The guess of Treg involvement in SSc pathogenesis came from the observation of a slightly lower Tregs expression in the skin of scleroderma patients compared with healthy controls and patients with local skin disease [ 31 , 32 , 33 , 34 ]. This led to suppose a low activity of T-regs in favor of T effector cells (Teff) in this disease [ 35 ].…”

“…This led to suppose a low activity of T-regs in favor of T effector cells (Teff) in this disease [ 35 ]. Tregs are characterized by heterogeneity and plasticity, which allow them to switch to effector T cells (T-eff), particularly Th17 cells, under the stimulus of IL-6 and IL-1β, which are usually highly expressed in inflammation [ 31 , 32 , 33 , 34 ].…”