Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis

• DOI: 10.1016/j.jaut.2011.02.009
• Publication Date: 2011-04-14T23:13:17Z
• Authors: G. Thangavelu; J.C. Parkman; C.L. Ewen; R.R.E. Uwiera; T.A. Baldwin; C.C. Anderson
• Keywords: Male; 0303 health sciences; T-Lymphocytes; Immunology; Programmed Cell Death 1 Receptor; Autoimmunity; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Co-inhibition; Self Tolerance; PD-1; Antigens, Surface; Immunology and Allergy; Animals; Homeostasis; Female; Apoptosis Regulatory Proteins; Tolerance; Thymic selection

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.