Jeniffer D Loaiza Naranjo, Vivian Zhang, Rathna Ravichandran, Anne-Sophie Bergot, Ranjeny Thomas, Emma E Hamilton-Williams
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引用次数: 0
Abstract
Loss of T-cell tolerance to multiple islet antigens is a key feature of autoimmune type 1 diabetes. In this study, we investigated the requirement for programmed death 1 (PD-1) expression by CD4+ T cells in the maintenance of self-tolerance via bystander suppression of autoreactive CD8+ T cells using nonobese diabetic mice. We used CRISPR/Cas9 to selectively knockout PD-1 in islet antigen-specific BDC2.5 CD4+ T cells and observed the impact on bystander tolerance of 8.3 CD8+ T cells, specific for a different islet antigen. Loss of PD-1 promoted the proliferation, Th1-like effector-memory phenotype, islet infiltration and expression of cytotoxic markers by BDC2.5 cells. PD-1-deficient BDC2.5 cells were impaired in their regulation of 8.3 cells, which proliferated more, developed an effector-memory phenotype and increased expression of effector molecules. While antigen-presenting cell maturation and migration into the pancreatic lymph node were not impacted by loss of PD-1 expression from BDC2.5 cells, migration of BDC2.5 cells out of the lymph node was required for enhanced activation of the CD8+ T cells. Together, these events led to accelerated diabetes progression, suggesting that PD-1 expression by CD4+ T cells promotes a tolerogenic microenvironment and restraining autoreactive CD8+ T cells.
期刊介绍:
The Australasian Society for Immunology Incorporated (ASI) was created by the amalgamation in 1991 of the Australian Society for Immunology, formed in 1970, and the New Zealand Society for Immunology, formed in 1975. The aim of the Society is to encourage and support the discipline of immunology in the Australasian region. It is a broadly based Society, embracing clinical and experimental, cellular and molecular immunology in humans and animals. The Society provides a network for the exchange of information and for collaboration within Australia, New Zealand and overseas. ASI members have been prominent in advancing biological and medical research worldwide. We seek to encourage the study of immunology in Australia and New Zealand and are active in introducing young scientists to the discipline.