Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis by the Expansion of CD4+CD25+ Regulatory T Cells

Abstract

There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4(+)CD25(+) T cells included both CD4(+)CD25(+)CD45RB(Low) (regulatory) and CD4(+)CD25(+)CD45RB(High) (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4(+)CD25(+)CD45RB(Low) T cells compared with mice immunized with mTg alone. CD4(+)CD25(+)CD45RB(Low) T cells expressed much higher levels of the forkhead family transcription factor, IL-10, and TGFbeta1 than CD4(+)CD25(+)CD45RB(High) T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the unfractionated CD4(+)CD25(+) T cells. Furthermore, transfer of these cells into CBA/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4(+)CD25(+)CD45RB(Low) T cells were more effective at suppressing histological thyroiditis than unfractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4(+)CD25(+)CD45RB(Low) T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease.

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

“…3B). Wang et al (20) reported that the administration of rTRAIL induced CD4 + CD25 + Tregs in mice that were immunized with thyroglobulin to develop EAT. These in vivo observations collectively suggest that the proliferative effect of TRAIL on Tregs becomes apparent when exposed to the risk for autoimmunity.…”

“…Furthermore, TRAIL on ES-DCs enhanced the proliferation of CD4 + CD25 + Tregs in vitro (19). With regard to the relationship between TRAIL and Tregs, TRAIL was shown to expand CD4 + CD25 + Tregs in a study of experimental autoimmune thyroiditis (EAT) (20). With regard to the ability of TRAIL to induce cell proliferation, it was recently reported that TRAIL promotes the proliferation of vascular smooth muscle cells and carcinoma cells (21,22).…”

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

“…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.…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…www.eje-online.org downregulating the proliferation of CD4 C CD25 C cells, a Treg subpopulation involved in the control of autoimmunity (116) and of thyroid cell apoptosis (117). Experimentally, the immune actions of leptin have been shown in several autoimmune rheumatic diseases (118).…”