title: Interindividual variation in human T regulatory cells.
abstract: FOXP3(+) regulatory T (Treg) cells enforce immune self-tolerance and homeostasis, and variation in some aspects of Treg function may contribute to human autoimmune diseases. Here, we analyzed population-level Treg variability by performing genome-wide expression profiling of CD4(+) Treg and conventional CD4(+) T (Tconv) cells from 168 donors, healthy or with established type-1 diabetes (T1D) or type-2 diabetes (T2D), in relation to genetic and immunologic screening. There was a range of variability in Treg signature transcripts, some almost invariant, others more variable, with more extensive variability for genes that control effector function (ENTPD1, FCRL1) than for lineage-specification factors like FOXP3 or IKZF2. Network analysis of Treg signature genes identified coregulated clusters that respond similarly to genetic and environmental variation in Treg and Tconv cells, denoting qualitative differences in otherwise shared regulatory circuits whereas other clusters are coregulated in Treg, but not Tconv, cells, suggesting Treg-specific regulation of genes like CTLA4 or DUSP4. Dense genotyping identified 110 local genetic variants (cis-expression quantitative trait loci), some of which are specifically active in Treg, but not Tconv, cells. The Treg signature became sharper with age and with increasing body-mass index, suggesting a tuning of Treg function with repertoire selection and/or chronic inflammation. Some Treg signature transcripts correlated with FOXP3 mRNA and/or protein, suggesting transcriptional or posttranslational regulatory relationships. Although no single transcript showed significant association to diabetes, overall expression of the Treg signature was subtly perturbed in T1D, but not T2D, patients.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferraro
authors.forename: Anna Morena
authors.initials: AM
authors.lastname: D'Alise
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Natasha
authors.initials: N
authors.lastname: Asinovski
authors.forename: Roxanne
authors.initials: R
authors.lastname: Phillips
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Replogle
authors.forename: Angelina
authors.initials: A
authors.lastname: Bernier
authors.forename: Lori
authors.initials: L
authors.lastname: Laffel
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D019070:Cell Lineage; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D012333:RNA, Messenger
keywords: immunoregulation; suppression