Human CD25+ regulatory T cells: two subsets defined by the integrins α4β7 or α4β1 confer distinct suppressive properties upon CD4+ T helper cells

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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(Thsup), which inhibit T cell activation via soluble mediators. Here, we describe two distinct subsets of human Tregs, characterized by expression of either the α4β7 integrin or the α4β1 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: α4β7+Tregs induce IL-10-producing Thsup (Tr1-like), whereas α4β1+ Tregs induce TGF-β-producing Thsup (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 Thsup via the soluble factors IL-10 and TGF-β.