title: Allospecific CD4(+) T cells retain effector function and are actively regulated by Treg cells in the context of transplantation tolerance.
abstract: Although donor-specific transfusion (DST) plus CD154 blockade represents a robust protocol for inducing transplantation tolerance, the underlying mechanisms are incompletely understood. In a murine T-cell adoptive transfer model, we have visualized alloantigen-specific, TCR-transgenic for H2-A(b) /H2-K(d) 54-68 epitope (TCR75) CD4(+) T cells with indirect allospecificity during the course of tolerance induction. Three main observations were made. First, although the majority of TCR75 CD4(+) T cells were deleted following DST plus CD154 blockade, the surviving TCR75 CD4(+) T cells were capable of making IL-2, upregulating CD44, and undergoing cell division, suggesting that they were functionally active. Indeed, residual TCR75 CD4(+) T cells reisolated from the primary recipients given DST plus CD154 blockade were fully capable of rejecting allografts upon secondary transfer. Second, in tolerant mice, TCR75 CD4(+) T cells were not induced to express Foxp3 in the graft-draining lymph node. TCR75 CD4(+) T cells were also absent in accepted graft tissues in which endogenous Treg cells were enriched. Finally, DST plus CD154 blockade resulted in an abortive expansion of TCR75 CD4(+) T cells, a process that required the presence of endogenous Treg cells. Collectively, surviving TCR75 CD4(+) T cells are immunocompetent but kept in check by an endogenous immunosuppressive network induced by DST plus CD154 blockade.
authors.affiliation: MRC Centre for Transplantation, King's College London, London, UK.|Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.affiliation: MRC Centre for Transplantation, King's College London, London, UK.
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.affiliation: Department of Pathology, University of Alabama, Birmingham, AL, USA.
authors.forename: R Pat
authors.initials: RP
authors.lastname: Bucy
authors.affiliation: MRC Centre for Transplantation, King's College London, London, UK.|Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH, USA.
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
authors.affiliation: MRC Centre for Transplantation, King's College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Lechler
authors.affiliation: MRC Centre for Transplantation, King's College London, London, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
keywords: CD4 T cells; CD40L blockade; Tolerance; Transplantation; Treg