title: IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes.
abstract: High expression of IL-21 and/or IL-21R has been described in T cell-mediated inflammatory diseases characterized by defects of counterregulatory mechanisms. CD4(+)CD25(+) regulatory T cells (Treg) are a T cell subset involved in the control of the immune responses. A diminished ability of these cells to inhibit T cell activation has been documented in immune-inflammatory diseases, raising the possibility that inflammatory stimuli can block the regulatory properties of Treg. We therefore examined whether IL-21 controls CD4(+)CD25(+) T cell function. We demonstrate in this study that IL-21 markedly enhances the proliferation of human CD4(+)CD25(-) T cells and counteracts the suppressive activities of CD4(+)CD25(+) T cells on CD4(+)CD25(-) T cells without affecting the percentage of Foxp3(+) cells or survival of Treg. Additionally, CD4(+)CD25(+) T cells induced in the presence of IL-21 maintain the ability to suppress alloresponses. Notably, IL-21 enhances the growth of CD8(+)CD25(-) T cells but does not revert the CD4(+)CD25(+) T cell-mediated suppression of this cell type, indicating that IL-21 makes CD4(+) T cells resistant to suppression rather than inhibiting CD4(+)CD25(+) T cell activity. Finally, we show that IL-2, IL-7, and IL-15, but not IL-21, reverse the anergic phenotype of CD4(+)CD25(+) T cells. Data indicate that IL-21 renders human CD4(+)CD25(-) T cells resistant to Treg-mediated suppression and suggest a novel mechanism by which IL-21 could augment T cell-activated responses in human immune-inflammatory diseases.
authors.affiliation: Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier 1, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peluso
authors.forename: Massimo Claudio
authors.initials: MC
authors.lastname: Fantini
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Monica
authors.initials: M
authors.lastname: Boirivant
authors.forename: Thomas T
authors.initials: TT
authors.lastname: MacDonald
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21