title: Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells.
abstract: Down-regulation of autoreactive T cell responses in vivo includes cell-contact-dependent as well as contact-independent mechanisms. Infectious tolerance is a contact-dependent mechanism used by naturally occurring CD25(+) T regulatory cells (Tregs) to confer suppressive activity upon conventional CD4(+) T cells thereby generating secondary T helper suppressor cells(Th(sup)), which inhibit T cell activation via soluble mediators. Here, we describe two distinct subsets of human Tregs, characterized by expression of either the alpha(4)beta(7) integrin or the alpha(4)beta(1) integrin. Upon activation, both subsets show an enhanced expression of FoxP3, recently described as a key transcription factor of murine Tregs. In addition, both are able to convey suppressive capacity to conventional CD4(+) T cells. However, the properties of Treg subsets are rather distinct: alpha(4)beta(7) (+)Tregs induce IL-10-producing Th(sup) (Tr1-like), whereas alpha(4)beta(1) (+) Tregs induce TGF-beta-producing Th(sup) (Th3-like). Our findings reconcile conflicting results by clearly demonstrating that suppression through naturally occurring CD25(+) Tregs is primary cell-contact-dependent but is subsequently followed by cell-contact-independent T cell inhibition mediated by second-generation Tr1- and Th3-like Th(sup) via the soluble factors IL-10 and TGF-beta.
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.forename: Sabine
authors.initials: S
authors.lastname: Fondel
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Christoph
authors.initials: C
authors.lastname: Richter
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Jan
authors.initials: J
authors.lastname: Kubach
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knop
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Enk
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitt
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016023:Integrins; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10