Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

Abstract

TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4+CD25+ regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-γ–producing CD4+ T (Th1) cells, and a lower frequency of CD4+Foxp3+ Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4+CD25+ Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4+CD25+ Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc-TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs.

The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages

“…5D, Table I), which was recently localized mainly to the syncytiotrophoblast within the placenta (28). TRAIL was shown to preferentially expand the Treg population and to inhibit expansion of the non-Treg cell pool in a mouse model (29). Because we observed that PE CM significantly reduced the viability of unstimulated CD4 + T cells (Fig.…”

“…In contrast, IL-10 was recently reported to upregulate the antiapoptotic Bcl-2 specifically in Tregs, but not in conventional T cells, suggesting a mechanism for IL-10-driven maternal Treg expansion during pregnancy (54). Similarly, the apoptosis-inducing factor TRAIL was shown to expand the Treg pool and to inhibit the expansion of non-Tregs (29). Thus, both IL-10 and TRAIL could increase the proportion of Tregs by preferentially promoting the survival of already existing Tregs.…”

“…The importance of TGF-b signaling in maintaining T cell homeostasis was described in a mouse model with T cell-specific deletion of TGF-bRII, in which lethal inflammation developed in association with T cell activation and disrupted Treg induction (55). Similarly, TRAIL was shown to mediate protection against autoimmune diseases in mice by promoting the expansion of Tregs (29,56). Thus, given the importance of immune tolerance during pregnancy, it is likely that TGF-b and TRAIL, as described for IL-10 (47, 48), contribute to the protection against uncontrolled immune cell activation and fetal loss.…”

Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context

“…Interestingly, blocking both TNF and OX40L in ins-HA mice did not fully inhibit the Teff→Treg boost (data not shown), suggesting that other molecules were involved. Some of them may belong to the TNFR family, such as death receptor 3, death receptor 5, or glucocorticoid-induced TNFR family-related protein because these molecules are able to promote Treg cell expansion (35)(36)(37)(38)(39). Thus, molecular mechanisms of the Teff→ Treg boost are diverse and differ depending on the tissue and the type of inflammation.…”

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

“…6C-E (Chen et al, 2003;Rao et al, 2005). In contrast, the apoptosis-inducing factor TRAIL may promote the preferential expansion of an already existing Treg cell population while inhibiting expansion of non-Treg cells, as shown in a mouse model (Ikeda et al, 2010). IL-10 may also promote the preferential survival of Treg cells by specifically upregulating the anti-apoptotic Bcl-2 in Treg cells but not in conventional T cells (Santner-Nanan et al, 2013).…”