IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy. J Immunol 2012 Dec 15;189(12):5638-48
Date
11/06/2012Pubmed ID
23125413Pubmed Central ID
PMC3537488DOI
10.4049/jimmunol.1200936Scopus ID
2-s2.0-84871173673 (requires institutional sign-in at Scopus site) 70 CitationsAbstract
"Natural" regulatory T cells (nTregs) that express the transcription factor Foxp3 and produce IL-10 are required for systemic immunological tolerance. "Induced" regulatory T cells (iTregs) are nonredundant and essential for tolerance at mucosal surfaces, yet their mechanisms of suppression and stability are unknown. We investigated the role of iTreg-produced IL-10 and iTreg fate in a treatment model of inflammatory bowel disease. Colitis was induced in Rag1(-/-) mice by the adoptive transfer of naive CD4(+) T cells carrying a nonfunctional Foxp3 allele. At the onset of weight loss, mice were treated with both iTregs and nTregs where one marked subset was selectively IL-10 deficient. Body weight assessment, histological scoring, cytokine analysis, and flow cytometry were used to monitor disease activity. Transcriptional profiling and TCR repertoire analysis were used to track cell fate. When nTregs were present but IL-10 deficient, iTreg-produced IL-10 was necessary and sufficient for the treatment of disease, and vice versa. Invariably, ∼85% of the transferred iTregs lost Foxp3 expression (ex-iTregs) but retained a portion of the iTreg transcriptome, which failed to limit their pathogenic potential upon retransfer. TCR repertoire analysis revealed no clonal relationships between iTregs and ex-iTregs, either within mice or between mice treated with the same cells. These data identify a dynamic IL-10-dependent functional reciprocity between regulatory T cell subsets that maintains mucosal tolerance. The niche supporting stable iTregs is limited and readily saturated, which promotes a large population of ex-iTregs with pathogenic potential during immunotherapy.
Author List
Schmitt EG, Haribhai D, Williams JB, Aggarwal P, Jia S, Charbonnier LM, Yan K, Lorier R, Turner A, Ziegelbauer J, Georgiev P, Simpson P, Salzman NH, Hessner MJ, Broeckel U, Chatila TA, Williams CBAuthors
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMartin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Director, Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Amy Turner Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ke Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Differentiation
Colitis
Disease Models, Animal
Forkhead Transcription Factors
Immune Tolerance
Inflammatory Bowel Diseases
Interleukin-10
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Transgenic
Mutagenesis, Insertional
Recombinant Fusion Proteins
T-Lymphocytes, Regulatory
Transcriptome