title: A major role for Bim in regulatory T cell homeostasis.
abstract: We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the proapoptotic molecule Bim compared with Treg from young mice. Furthermore, in the absence of Bim, Treg accumulate rapidly, accounting for >25% of the CD4(+) T cell compartment by 6 mo of age. Additionally, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bim(lo) Treg. Collectively, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts.
authors.affiliation: Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. Claire.Chougnet@cchmc.org
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.forename: Pulak
authors.initials: P
authors.lastname: Tripathi
authors.forename: Celine S
authors.initials: CS
authors.lastname: Lages
authors.forename: Jana
authors.initials: J
authors.lastname: Raynor
authors.forename: Allyson
authors.initials: A
authors.lastname: Sholl
authors.forename: Pamela
authors.initials: P
authors.lastname: Fink
authors.forename: David R
authors.initials: DR
authors.lastname: Plas
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins