Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. We showed that IL-10-secreting Tregs can be delineated in normal mice as CD4+CD25-Foxp3- T cells that express lymphocyte activation gene-3 (LAG-3), an MHC class II-binding CD4 homolog. CD4+CD25-LAG3+ Tregs characteristically express early growth response gene-2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4+ T cells into IL-10-secreting and LAG-3-expressing Tregs. Moreover, CD4+CD25-LAG3+ Tregs show B cell-dependent development. CD4+CD25-LAG3+ Tregs, but not CD4+CD25+ Tregs, strongly suppressed the antibody production in B cells co-cultured with helper T cells. Thus, IL-10-secreting Egr-2+LAG3+CD4+ Tregs are closely related to B cells and can be exploited for the treat ment of autoimmune diseases.
Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease that affects many organs, and the immunological disorders are accompanied by autoantibody production. Recent case-control association study revealed that polymorphisms in the Egr-2 influence SLE susceptibility in humans. Interestingly, adoptive transfer of CD4+CD25-LAG3+ Tregs from MRL/+ mice suppressed autoantibody production and the progression of nephritis in MRL/lpr lupus prone mice. In contrast, CD4+CD25+ Tregs from MRL/+ mice exhibited no significant therapeutic effect upon transfer to MRL/lpr mice. These results indicate that CD4+CD25-LAG3+ Tregs play key roles in the regulation of humoral immunity by the strong suppressive activity for B cell antibody production.