[Seminar] Maintenance of regulatory T cell stability by ubiquitin E3 ligases deltex1 and XIAP by Prof. Ming-Zong Lai

Abstract:

Regulatory T cells (Tregs) are one of the major mechanisms underlying peripheral immune tolerance. The persistent expression of the master transcription factor Foxp3 is essential for the suppressive function of Tregs. In addition, Tregs are subjected to re-programmed into Tregs that secreting inflammatory cytokines including IFN-g and IL-17. How Treg stability is maintained in vivo remained incompletely understood.

We identify an essential role of E3 ligase deltex1 (DTX1) in maintaining Treg in vivo stability. Mice with Treg-specific knockout of DTX1 exhibit T cell over-activation and autoantibody production. In in vitro analysis, Dtx1^-/- Tregs are as effective as WT Tregs in suppression T effector activation. However, Dtx1^-/- Tregs are unable to inhibit effector T-induced colitis and airway hypersensitivity. The expression of Treg master transcription factor Foxp3 is down-regulated in Dtx1^-/- Tregs after adoptive transfer. We further find an antagonism between DTX1 and HIF-1a, DTX1 binds HIF-1a and promotes HIF-1a protein degradation. Consequently, DTX1 effectively protects Foxp3 from HIF-1a-mediated downregulation in inflammatory tissues. This finding reveals that DTX1 exerts another level of control on Treg stability in vivo by sustaining the expression of Foxp3 protein in Tregs.

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease linked to mutation of E3 ligase X-linked inhibitor of apoptosis protein (XIAP), with molecular mechanism incompletely understood. We also identify a role of XIAP in maintaining Tregs stability by using XLP-2 mouse model. We show that mouse Xiap^-/- Tregs and human XIAP-deficient Tregs are defective in suppressive function. The Xiap^-/- Tregs defect is linked to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap^-/- Treg cells. In addition, Xiap^-/- Tregs are prone to IFN-g and IL-17 secretion. Transfer of XIAP-sufficient wild-type Tregs partly rescues infection-induced inflammation in Xiap^-/- mice. Furthermore, inflammation-induced reprogramming of Xiap^-/- Tregs can be prevented by blockade of the IL-6 receptor (IL-6R) in vitro and in vivo, and a combination of anti-IL-6R and Xiap^-/- Tregs confers survival to inflammatory infection in Xiap^-/- mice. Our results illustrate that inflammation-induced Tregs instability could be corrected by blockade of IL-6R, suggesting that, in combination with anti-IL-6R, even destabilized Tregs could be used in therapeutic application.

Research Interests:

The primary interests of my lab are on the immune cell signaling and the balance between T cell tolerance and inflammation, as the basis for control of autoimmune and autoinflammatory diseases. We have worked on the integration T cell activation signals and the cross-coupling between activation and apoptotic signals. Ongoing focus is on the immune tolerance maintained by regulatory T cells and T cell anergy, and on the resolution of inflammation. We have identified new pathways in the modulation of regulatory T cells, inflammatory Th17 cells, and activation of inflammasome and myeloid cells. We characterized on how regulation of HIF-1a controls the function of Th17 cells and regulatory T cells. We further delineated the mechanisms underlying the plasticity of regulatory T cells, conversion into inflammatory T cells, and developed new approach to maintain stability. We identify three molecules that regulate T cell tolerance, deltex1 (DTX1), death-associated protein kinase (DAPK) and X-linked inhibitor of apoptosis protein (XIAP).