title: Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis.
abstract: Regulatory T-cells (Tregs) are vital for maintaining immunological self-tolerance, and the transcription factor FOXP3 is considered critical for their development and function. Peripheral Treg induction may significantly contribute to the total Treg pool in healthy adults, and this pathway may be enhanced in thymic-deficient conditions like multiple sclerosis (MS). Here, we evaluated iTreg formation from memory versus naïve CD4(+)CD25(-) T-cell precursors. We report the novel finding that memory T-cells readily expressed CD25 and FOXP3, and demonstrated significantly greater suppressive function. Additionally, the CD25(-)FOXP3(-) fraction of stimulated memory T-cells also displayed robust suppression not observed in naïve counterparts or ex vivo resting (CD25(-)) T-cells. This regulatory population was present in both healthy subjects and clinically-quiescent MS patients, but was specifically deficient during disease exacerbation. These studies indicate that iTreg development and function are precursor dependent. Furthermore, MS quiescence appears to correlate with restoration of suppressive function in memory-derived CD4(+)CD25(-)FOXP3(-) iTregs.
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Imran H
authors.initials: IH
authors.lastname: Mohiuddin
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Pillai
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Baughman
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Greenberg
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.affiliation: Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Crawford
authors.affiliation: Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA. Electronic address: nitin-karandikar@uiowa.edu.
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D000208:Acute Disease; D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D061251:Primary Cell Culture; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D000906:Antibodies; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit
keywords: FOXP3; Immune regulation; Memory; Multiple sclerosis; Naïve; T cells