B cell tolerance to epidermal ribonuclear-associated neo-autoantigen in vivo

Summary

Defining how self-antigens are perceived by the immune system is pivotal to understand how tolerance is maintained under homeostatic conditions. Clinically relevant, natural autoantigens targeted by autoantibodies in e.g. systemic lupus erythematosus (SLE) commonly have an intrinsic ability to engage not only the B cell receptor (BCR), but also a costimulatory pathway in B cells, such as the TLR7 pathway. Here we developed a novel mouse model displaying inducible expression of a fluorescent epidermal neo-autoantigen carrying an OT-II T cell epitope, B cell antigen, and associated ribonucleic acids capable of stimulating TLR7. The neo-autoantigen was expressed in skin, but did not drain in intact form into draining lymph nodes, even after UVB stimulated induction of apoptosis in the basal layer. Adoptively transferred autoreactive B cells were follicularly excluded and perished at the T-B border in the spleen, preventing their recirculation and encounter with antigen peripherally. This transitional check-point was bypassed by crossing the reporter to a BCR knock-in line on a C4 deficient background. Adoptively transferred OT-II T cells rapidly homed into cutaneous lymph nodes and upregulated CD69. Yet surprisingly, tolerance was not broken, as the T cells subsequently downregulated activation markers and contracted. Our results highlight how sequestration of intracellular and peripheral antigen, the transitional B cell tolerance check-point, and T cell regulation cooperate to maintain immunological tolerance in vivo. This article is protected by copyright. All rights reserved.