title: Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells.
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.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Langenhorst
authors.forename: Tea
authors.initials: T
authors.lastname: Gogishvili
authors.forename: Eliana
authors.initials: E
authors.lastname: Ribechini
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: Kirsty
authors.initials: K
authors.lastname: McPherson
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018106:CD28 Antigens / Q000819:agonists / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; C515371:Ccr7 protein, mouse; C556062:IL10 protein, mouse; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D016753:Interleukin-10