1. Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells.
- Author
-
Langenhorst D, Gogishvili T, Ribechini E, Kneitz S, McPherson K, Lutz MB, and Hünig T
- Subjects
- Animals, Antibodies immunology, CD28 Antigens agonists, Cell Differentiation drug effects, Cell Movement drug effects, Cells, Cultured, Clone Cells, Gene Expression drug effects, Inflammation immunology, Inflammation metabolism, Interleukin-10 biosynthesis, Interleukin-10 immunology, Lymph Nodes cytology, Lymph Nodes drug effects, Lymph Nodes immunology, Lymphocyte Activation drug effects, Mice, Mice, Inbred C57BL, Receptors, CCR5 genetics, Receptors, CCR5 immunology, Receptors, CCR7 genetics, Receptors, CCR7 immunology, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory drug effects, Antibodies pharmacology, Apoptosis drug effects, CD28 Antigens immunology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory immunology
- Abstract
The ability of CD4(+)Foxp3(+) regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7(+)CCR5(-) lymph node-seeking to a CCR7(-)CCR5(+) inflammation-seeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.
- Published
- 2012
- Full Text
- View/download PDF