title: Differential role of naïve and memory CD4 T-cell subsets in primary alloresponses.
abstract: The T cell response to major histocompatibility complex (MHC) alloantigens occurs via two main pathways. The direct pathway involves the recognition of intact allogeneic MHC:peptide complexes on donor cells and provokes uniquely high frequencies of responsive T cells. The indirect response results from alloantigens being processed like any other protein antigen and presented as peptide by autologous antigen-presenting cells. The frequencies of T cells with indirect allospecificity are orders of magnitude lower and comparable to other peptide-specific responses. In this study, we explored the contributions of naïve and memory CD4(+) T cells to these two pathways. Using an adoptive transfer and skin transplantation model we found that naive and memory CD4(+) T cells, both naturally occurring and induced by sensitization with multiple third-party alloantigens, contributed equally to graft rejection when only the direct pathway was operative. In contrast, the indirect response was predominantly mediated by the naïve subset. Elimination of regulatory CD4(+)CD25(+) T cells enabled memory cells to reject grafts through the indirect pathway, but at a much slower tempo than for naïve cells. These findings have implications for better targeting of immunosuppression to inhibit immediate and later forms of alloimmunity.
authors.affiliation: Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland. Dela.Golshayan@chuv.ch
authors.forename: D
authors.initials: D
authors.lastname: Golshayan
authors.forename: J-C
authors.initials: JC
authors.lastname: Wyss
authors.forename: M
authors.initials: M
authors.lastname: Buckland
authors.forename: M
authors.initials: M
authors.lastname: Hernandez-Fuentes
authors.forename: R I
authors.initials: RI
authors.lastname: Lechler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens