title: Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis.
abstract: Lymphopenia driven T cell activation is associated with autoimmunity. That lymphopenia does not always lead to autoimmunity suggests that control mechanisms may exist. We assessed the importance of the co-inhibitory receptor programmed death-1 (PD-1) in the control of lymphopenia-driven autoimmunity in newly generated T cells vs. established peripheral T cells and in thymic selection. PD-1 was not required for negative selection in the thymus or for maintenance of self tolerance following transfer of established PD-1⁻/⁻ peripheral T cells to a lymphopenic host. In contrast, PD-1 was essential for systemic self tolerance in newly generated T cells under lymphopenic conditions, as PD-1⁻/⁻ recent thymic emigrants (RTE), generated after transfer of PD-1⁻/⁻ hematopoietic stem cell (HSC) precursors or thymocytes into lymphopenic adult Rag⁻/⁻ recipients, induced a rapidly lethal multi-organ inflammatory disease. Disease could be blocked by using lymph node deficient recipients, indicating that lymphopenia driven PD-1⁻/⁻ T cell activation required access to sufficient lymph node stroma. These data suggested that PD-1⁻/⁻ mice themselves might be substantially protected from autoimmunity because their T cell repertoire is first generated early in life, a period naturally deficient in lymph node stroma. Consistent with this idea, neonatal Rag⁻/⁻ recipients of PD-1⁻/⁻ HSC were resistant to disease. Thus, a critical role of PD-1 resides in the control of RTE in lymphopenia. The data suggest that PD-1 and a paucity of lymphoid stroma cooperate to control autoimmunity in newly generated T cells. Clinical therapies for autoimmune disease employing lymphoablation and hematopoietic stem cell transplantation will need to take into account functional polymorphisms in the PD-1 pathway, if the treatment is to ameliorate rather than exacerbate autoimmunity.
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: G
authors: G
authors: Thangavelu
authors: J C
authors: JC
authors: Parkman
authors: C L
authors: CL
authors: Ewen
authors: R R E
authors: RR
authors: Uwiera
authors: T A
authors: TA
authors: Baldwin
authors: C C
authors: CC
authors: Anderson
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015551:Autoimmunity / Q000276:immunology*; D005260:Female; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor