期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 4, 页码 1301-1310出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801206
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资金
- National Institutes of Health [P30 CA56036, R01 CA204881, R01 CA206026]
- Department of Defense Congressionally Directed Medical Research Programs [W81XWH-17-1-0299]
- Targeted Diagnostic & Therapeutics, Inc.
- Courtney Ann Diacont Memorial Foundation
- PhRMA Foundation
- W.W. Smith Charitable Trust
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health [SAP 4100059197, SAP 4100051723]
Characterizing self-tolerance mechanisms and their failure is critical to understand immune homeostasis, cancer immunity, and autoimmunity. However, examination of self-tolerance mechanisms has relied primarily on transgenic mice expressing TCRs targeting well-characterized, but nonphysiologic, model Ags, such as OVA and hemagglutinin. Identifying TCRs directed against bona fide self-antigens is made difficult by the extraordinary diversity of TCRs and the low prevalence of Ag-specific clones (< 10-100 naive cells per organism), limiting dissection of tolerance mechanisms restricting immunity to self-proteins. In this study, we isolated and characterized TCRs recognizing the intestinal epithelial cell receptor and colorectal cancer Ag GUCY2C to establish a model to study self-antigen-specific tolerance mechanisms. GUCY2C-specific CD4(+) effector T cells were isolated from immunized, nontolerant Gucy2c(-/-) mice. Next-generation sequencing identified GUCY2C-specific TCRs, which were engineered into CD4(+) T cells in vitro to confirm TCR recognition of GUCY2C. Further, the generation of retrogenic mice by reconstitution with TCR-transduced hematopoietic stem cells resulted in normal CD4(+) T cell development, responsiveness to immunization, and GUCY2C-induced tolerance in recipient mice, recapitulating observations in conventional models. This retrogenic model can be employed to define self-tolerance mechanisms restricting T and B cell responses to GUCY2C to optimize colorectal cancer immunotherapy without autoimmunity.
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