The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells

Abstract

Mechanisms linking innate immunity and autoimmune responses are poorly understood1. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.

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Figure 1: Impaired development of CD40L-induced systemic autoimmunity in Cd40lg × S100A9−/− mice.
Figure 2: Mrp8 and Mrp14 proteins are required for the induction of autoreactivity in CD8+ T cells.
Figure 3: MRP8 and MRP14 abundance is increased in subjects with lupus erythematosus, and they upregulate IL-17 expression in CD8+ T cells.
Figure 4: Essential role of TLR4 for Mrp8-mediated effects on CD8+ T cells in the induction of autoreactivity.

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Acknowledgements

We would like to thank H. Hinte and C. Solé for excellent technical assistance. This work was supported by the Interdisciplinary Center of Clinical Research grant Lo2/017/07 to K.L. and S.B. as well as grant Vo2/014/09 to T.V., by the German Cancer Society grant 107891 to K.L. and S.B., by the Federal Ministry of Education and Research, project AID-Net to J.R. and by the German Research Association grant Lo817/2-1 to K.L. and S.B.

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K.L. conceived of the study, performed the experiments, analyzed data, prepared the figures and wrote the paper. T.V. provided recombinant Mrp8 and Mrp14 proteins as well as Mrp8- and Mrp14-specific antibodies, performed Mrp-specific ELISAs and helped to design some of the experiments. M.V., V.K. and L.K. assisted K.L. with some experiments; A.L. and D.F. provided Ager−/− mice; W.N. bred S100A9−/− mice; A.K. collected a few skin biopsies from subjects with lupus erythematosus; L.S. provided human kidney biopsies; T.A.L. provided most of the human skin biopsies and contributed advice in parts of the study; J.R. provided expertise and helped to design experiments and to write the paper; S.B. contributed expertise and helped to write the paper.

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Correspondence to Karin Loser.

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The authors declare no competing financial interests.

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Loser, K., Vogl, T., Voskort, M. et al. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med 16, 713–717 (2010). https://doi.org/10.1038/nm.2150

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