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.

Programmed Death-1 Shapes Memory Phenotype CD8 T Cell Subsets in a Cell-Intrinsic Manner

“…Given that most of these cells recognize self-ligands, although with low affinity (56), it is reasonable to think that they could have an autoreactive potential. In line with this hypothesis, Thangavelu et al (57), although not examining GzmB expression on T cells, have shown in a recent report that PD-1 KO recent thymic emigrants cause a lethal autoimmune-like disease in chronically lymphopenic hosts.…”

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

“…The PD-1 pathway is critical for both positive and negative selection of T cells in the thymus and is necessary for development of systemic selftolerance. [33][34][35][36] As such, previous PD-1 blockade could have longlasting effects on the thymus, resulting in altered PD-1 expression and imbalanced processing of the large number of T cells infused during HSCT. In addition, PD-1 blockade may alter posttransplant immune reconstitution through its effects on circulating cytokines and antigenpresenting cells.…”

Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation

“…Absence of PD-1 is associated with development of a multi-organ autoimmunity after lymphopenia-induced proliferation (LIP) [61]. Interestingly, the disorder was only developed by mice that were treated with PD-1 -/-hematopoietic stem cells (HSC), and not by those reconstituted with mature PD-1 -/-lymphocytes, indicating that the PD-1 expression is critical to establish self-tolerance of the recentthymic emigrants [61].…”