Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice. Issue 119 (May 2021)

• Record Type: Journal Article
• Authors: Khosravi-Maharlooei, Mohsen; Li, HaoWei; Hoelzl, Markus; Zhao, Guiling; Ruiz, Amanda; Misra, Aditya; Li, Yang; Teteloshvili, Nato; Nauman, Grace; Danzl, Nichole; Ding, Xiaolan; Pinker, Elisha Y.; Obradovic, Aleksandar; Yang, Yong-Guang; Iuga, Alina; Creusot, Remi J.; Winchester, Robert; Sykes, Megan
• Is Part Of: Journal of autoimmunity. Issue 119(2021)
• Publication Date: 2021-05
• Subjects: Humanized mouse -- Autoimmunity -- Thymic selection -- Regulatory T cell -- TCR repertoire -- Indirect antigen presentation; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2021.102612
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: We evaluated the role of the thymus in development of multi-organ autoimmunity in human immune system (HIS) mice. T cells were essential for disease development and the same T cell clones with varying phenotypes infiltrated multiple tissues. De novo -generated hematopoietic stem cell (HSC)-derived T cells were the major disease drivers, though thymocytes pre-existing in grafted human thymi contributed if not first depleted. HIS mice with a native mouse thymus developed disease earlier than thymectomized mice with a thymocyte-depleted human thymus graft. Defective structure in the native mouse thymus was associated with impaired negative selection of thymocytes expressing a transgenic TCR recognizing a self-antigen. Disease developed without direct recognition of antigens on recipient mouse MHC. While human thymus grafts had normal structure and negative selection, failure to tolerize human T cells recognizing mouse antigens presented on HLA molecules may explain eventual disease development. These new insights have implications for human autoimmunity and suggest methods of avoiding autoimmunity in next-generation HIS mice. Highlights: T cells are essential for development of multi-organ autoimmunity in humanized mice. Macrophages and De novo -generated T cells were the major disease drivers. Defective structure and impaired selection of thymocytes in the NSG mouse thymus. Lower regulatory T cells in native mouse thymus compared to grafted human thymus. Disease developed without direct recognition of antigens on recipient mouse MHC.