Year-end Sale % OFF 
Abstract
Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6‐deficient Tregs were dysfunctional in vivo; mice with Treg‐restricted deletion of TRAF6 were resistant to implanted tumors and displayed enhanced anti‐tumor immunity. We further determined that FOXP3 undergoes K63‐linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. In the absence of TRAF6 activity or upon mutation of the ubiquitination site, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63‐linked ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene‐regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg‐stabilizing regulator that may be targeted in novel tolerance‐breaking therapies.
Highlights
In order for the immune system to function properly, the targets and amplitude of immune responses must be tightly controlled
TRAF6 plays a potentially significant role in Treg biology. In line with this notion, high levels of TRAF6 transcript were found in naıve CD4+ T cells differentiating into Tregs in vitro, but not those committing to other T helper lineages (Fig 1A and Appendix Fig S1A)
We further found that naturally occurring Tregs freshly isolated from the peripheral blood of healthy human donors expressed TRAF6 mRNA to a greater degree than their non-Treg CD4+ counterparts (Fig 1B and Appendix Fig S1B)
Summary
In order for the immune system to function properly, the targets and amplitude of immune responses must be tightly controlled. Regulatory T cells (Tregs) are among the safeguards that prevent aberrant immune responses including those underlying autoimmunity, inflammatory diseases, or allergy (Sakaguchi et al, 2008). This critical function of Tregs is mediated by several suppressive mechanisms including production of anti-inflammatory cytokines (IL-10, TGFb, IL-35, etc.), expression of co-inhibitory receptors and ligands, and the disruption of effector cell division and metabolism (Vignali et al, 2008). The expansion or enhancement of Tregs may be an effective means to enforce immune tolerance to transplanted grafts or to restore immune homeostasis in patients suffering from autoimmune pathologies (Wang et al, 2011). A thorough understanding of the molecules and pathways important for the function
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
