| First Author | McDonald-Hyman C | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 10 | Pages | 4604-4621 |
| PubMed ID | 30106752 | Mgi Jnum | J:266942 |
| Mgi Id | MGI:6257109 | Doi | 10.1172/JCI95713 |
| Citation | McDonald-Hyman C, et al. (2018) The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease. J Clin Invest 128(10):4604-4621 |
| abstractText | Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-theta (PKC-theta) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-theta localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-theta phospho target and show that vimentin forms a DPC superstructure on which PKC-theta accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-theta inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-theta-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-theta inhibition is secondary to effects on vimentin, not just PKC-theta kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency. |
