title: PD-1 is not required for natural or peripherally induced regulatory T cells: Severe autoimmunity despite normal production of regulatory T cells.
abstract: The expression of the coinhibitor PD-1 on T cells is important for the establishment of immune homeostasis. We previously found that PD-1 is particularly critical for the control of self-tolerance during lymphopenia-induced proliferation of recent thymic emigrants (RTEs). Previous studies suggested that PD-1 modulates the generation of Treg cells, particularly peripherally induced Treg (pTreg) cells, and controls Th17 cells. However, these conclusions were derived indirectly from studies on the ligand PD-L1, and not PD-1 itself. Herein we directly tested whether T-cell PD-1 expression was needed for Treg cell generation and examined if a paucity of Treg cells or enhanced Th17 cells could explain the severe lymphopenia-potentiated autoimmunity caused by PD-1 KO RTEs. Employing the murine FoxP3(EGFP) reporter system to simultaneously monitor conversion of WT and PD-1 KO T cells to pTreg cells in the same animal, we found that PD-1 deficiency did not inhibit pTreg cell generation or lead to Th17-cell-mediated autoimmunity. Surprisingly, pTreg cell numbers were increased in PD-1 KO versus WT cell populations. Furthermore, we noted an increased conversion to pTreg cells by RTEs. Our data suggest that the primary role for PD-1 is to restrain T-cell activation/proliferation to self-Ags rather than promote generation of Treg cells.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes and Transplant Institutes, University of Alberta, Edmonton, AB, Canada.
authors.forename: Kristofor K
authors.initials: KK
authors.lastname: Ellestad
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Thangavelu
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Ewen
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Colin C
authors.initials: CC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D001324:Autoantigens; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: Autoimmunity; Coinhibition; Costimulation; Lymphopenia; Regulatory T cells; Tolerance