title: IL-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ regulatory T cells and allows expansion of alloreactive and autoreactive T cells.
abstract: CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) control the activation and expansion of alloreactive and autoreactive T cell clones. Because uncontrolled activation and expansion of autoreactive T cells occur in an IL-7-rich environment, we explored the possibility that IL-7 may affect the function of Treg. We show that the functional high-affinity IL-7R is expressed on both naive and memory Tregs, and exposure to IL-7 results in STAT-5 phosphorylation. Naive, but not memory, Tregs proliferated greatly and acquired a memory phenotype in the setting of a suppression assay when IL-7 was present. Importantly, the presence of IL-7 abrogated the capacity of Tregs to suppress proliferation of conventional T cells in response to TCR activators, including alloantigens and autoantigens. Removal of IL-7 restored the suppressive function of Tregs. Preblocking of the IL-7R on the Tregs also restored suppressor function, indicating that IL-7 directly affected Treg function. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T cells, thereby providing an additional mechanism for activating and expanding alloreactive and autoreactive T cells.
authors.affiliation: Center for Regenerative Therapies Dresden, Dresden University of Technology, 01307 Dresden, Germany.
authors.forename: Anne-Kristin
authors.initials: AK
authors.lastname: Heninger
authors.forename: Anke
authors.initials: A
authors.lastname: Theil
authors.forename: Carmen
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Cathleen
authors.initials: C
authors.lastname: Petzold
authors.forename: Nicole
authors.initials: N
authors.lastname: Huebel
authors.forename: Karsten
authors.initials: K
authors.lastname: Kretschmer
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Paolo
authors.initials: P
authors.lastname: Monti
mesh_terms: D001324:Autoantigens / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D000075202:Contraindications; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015851:Interleukin-7 / Q000502:physiology*; D007519:Isoantigens / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508017:IL2RA protein, human; C508605:IL7 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D007519:Isoantigens; D016753:Interleukin-10