title: CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets.
abstract: Immune tolerance and activation depend on precise control over the number and function of immunosuppressive Foxp3(+) regulatory T (T reg) cells, and the importance of IL-2 in maintaining tolerance and preventing autoimmunity is clear. However, the homeostatic requirement for IL-2 among specific populations of peripheral T reg cells remains poorly understood. We show that IL-2 selectively maintains a population of quiescent CD44(lo)CD62L(hi) T reg cells that gain access to paracrine IL-2 produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokine receptor CCR7. In contrast, CD44(hi)CD62L(lo)CCR7(lo) T reg cells that populate nonlymphoid tissues do not access IL-2-prevalent regions in vivo and are insensitive to IL-2 blockade; instead, their maintenance depends on continued signaling through the co-stimulatory receptor ICOS (inducible co-stimulator). Thus, we define a fundamental homeostatic subdivision in T reg cell populations based on their localization and provide an integrated framework for understanding how T reg cell abundance and function are controlled by unique signals in different tissue environments.
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Smigiel
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Richards
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.forename: Kerri R
authors.initials: KR
authors.lastname: Thomas
authors.forename: Jan C
authors.initials: JC
authors.lastname: Dudda
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klonowski
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
mesh_terms: D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D019899:Paracrine Communication / Q000276:immunology; D016133:Polymerase Chain Reaction; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C515371:Ccr7 protein, mouse; D007376:Interleukin-2; D054400:Receptors, CCR7