title: Reduced IL-2 expression in NOD mice leads to a temporal increase in CD62Llo FoxP3+ CD4+ T cells with limited suppressor activity.
abstract: IL-2 plays a critical role in the induction and maintenance of FoxP3-expressing regulatory T cells (FoxP3(+) Tregs). Reduced expression of IL-2 is linked to T-cell-mediated autoimmune diseases such as type 1 diabetes (T1D), in which an imbalance between FoxP3(+) Tregs and pathogenic T effectors exists. We investigated the contribution of IL-2 to dysregulation of FoxP3(+) Tregs by comparing wildtype NOD mice with animals congenic for a C57BL/6-derived disease-resistant Il2 allele and in which T-cell secretion of IL-2 is increased (NOD.B6Idd3). Although NOD mice exhibited a progressive decline in the frequency of CD62L(hi) FoxP3(+) Tregs due to an increase in CD62L(lo) FoxP3(+) Tregs, CD62L(hi) FoxP3(+) Tregs were maintained in the pancreatic lymph nodes and islets of NOD.B6Idd3 mice. Notably, the frequency of proliferating CD62L(hi) FoxP3(+) Tregs was elevated in the islets of NOD.B6Idd3 versus NOD mice. Increasing levels of IL-2 in vivo also resulted in larger numbers of CD62L(hi) FoxP3(+) Tregs in NOD mice. These results demonstrate that IL-2 influences the suppressor activity of the FoxP3(+) Tregs pool by regulating the balance between CD62L(lo) and CD62L(hi) FoxP3(+) Tregs. In NOD mice, reduced IL-2 expression leads to an increase in nonsuppressive CD62L(lo) FoxP3(+) Tregs, which in turn correlates with a pool of CD62L(hi) FoxP3(+) Tregs with limited proliferation.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Goudy
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Johnson
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Alaina
authors.initials: A
authors.lastname: Garland
authors.affiliation: Gene Therapy Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Gene Therapy Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.|UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D015870:Gene Expression; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology; D019041:L-Selectin / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D019041:L-Selectin