Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease
Hanspeter Waldner, Mary Collins, Vijay K. Kuchroo
Hanspeter Waldner, Mary Collins, Vijay K. Kuchroo
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Article Autoimmunity

Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease

Abstract

We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139–151, on the experimental autoimmune encephalomyelitis–resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell–activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.

Authors

Hanspeter Waldner, Mary Collins, Vijay K. Kuchroo

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Responses of 5B6 transgenic T cells to PLP139–151. (A) Proliferative res...
Responses of 5B6 transgenic T cells to PLP139–151. (A) Proliferative response of 5B6 transgenic T cells to PLP139–151 presented by DAS cells. CD4-enriched T cell samples from 5B6 transgenic SJL and B10.S mice were stimulated with the indicated numbers of PLP139–151–pulsed DAS cells. T cell proliferation was assessed by [3H]thymidine incorporation assay. The mean cpm ± SD of triplicate cultures are shown. (B) Proliferative response of T cells from 5B6 transgenic B10.S or SJL mice to PLP139–151 presented by syngeneic APCs. Splenocyte samples from unimmunized 5B6 transgenic and nontransgenic littermate (NLM) B10.S or SJL mice were enriched for CD4+ T cells and were cultured with irradiated splenocytes from nontransgenic littermates in the presence of the indicated concentrations of PLP139–151 or control peptide PLP178–191. Proliferative responses were determined by [3H]thymidine incorporation assay. The mean cpm ± SD of triplicate cultures of one experiment representative of three are shown. (C) IL-2 response to PLP139–151 of T cells from 5B6 transgenic B10.S or SJL mice. Supernatants from cultures in B were assayed in duplicate by ELISA for cytokine production. Representative data from one of three experiments are shown. (D) INF-γ response of spleen cells from 5B6 transgenic B10.S or SJL mice to PLP139–151 stimulation. Culture supernatants from 5B6 transgenic SJL or B10.S whole spleen cells stimulated with the indicated concentrations of PLP139–151 were assayed in duplicate by ELISA for INF-γ production.