title: IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age.
abstract: Regulatory T cells (Tregs), a subset of CD4(+) T cells, dramatically accumulate with age in humans and mice and contribute to age-related immune suppression. Recently, we showed that a majority of accumulating Tregs in aged mice expressed low levels of CD25, and their accrual is associated with declining levels of IL-2 in aged mice. In this study, we further investigated the origin of CD25(lo) Tregs in aged mice. First, aged Tregs had high expression of neuropilin-1 and Helios, and had a broad Vβ repertoire. Next, we analyzed the gene expression profile of Tregs, naive T cells, and memory T cells in aged mice. We found that the gene expression profile of aged CD25(lo) Tregs were more related to young CD25(lo) Tregs than to either naive or memory T cells. Further, the gene expression profile of aged Tregs was consistent with recently described "effector" Tregs (eTregs). Additional analysis revealed that nearly all Tregs in aged mice were of an effector phenotype (CD44(hi)CD62L(lo)) and could be further characterized by high levels of ICOS and CD69. ICOS contributed to Treg maintenance in aged mice, because in vivo Ab blockade of ICOSL led to a loss of eTregs, and this loss was rescued in Bim-deficient mice. Further, serum levels of IL-6 increased with age and contributed to elevated expression of ICOS on aged Tregs. Finally, Treg accrual was significantly blunted in aged IL-6-deficient mice. Together, our data show a role for IL-6 in promoting eTreg accrual with age likely through maintenance of ICOS expression.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Jana
authors.initials: J
authors.lastname: Raynor
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229; and.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Maha
authors.initials: M
authors.lastname: Almanan
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Kun-Po
authors.initials: KP
authors.lastname: Li
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 David.Hildeman@cchmc.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000037:antagonists & inhibitors; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D019041:L-Selectin / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039942:Neuropilin-1 / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D019041:L-Selectin; D037181:Lectins, C-Type; D008565:Membrane Proteins; D039942:Neuropilin-1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000099192:CD69 Antigens; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C476399:Cd44 protein, mouse; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; C508018:Il2ra protein, mouse; C491746:Zfpn1a2 protein, mouse; C577686:interleukin-6, mouse