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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Grewal, I.S. & Flavell, R.A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol. 16, 111–135 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Koshy, M., Berger, D. & Crow, M.K. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J. Clin. Invest. 98, 826–837 (1996).

    CAS  Article  Google Scholar 

  4. 4

    MacDonald, K.P., Nishioka, Y., Lipsky, P.E. & Thomas, R. Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J. Clin. Invest. 100, 2404–2414 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Grewal, I.S. et al. Requirement for CD40 ligand in co-stimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273, 1864–1867 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Mehling, A. et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J. Exp. Med. 194, 615–628 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Roth, J., Vogl, T., Sorg, C. & Sunderkötter, C. Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol. 24, 155–158 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Foell, D. & Roth, J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum. 50, 3762–3771 (2004).

    CAS  Article  Google Scholar 

  9. 9

    van Lent, P.L. et al. Myeloid-related proteins S100A8/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis. Ann. Rheum. Dis. 67, 1750–1758 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Broome, A.M., Ryan, D. & Eckert, R.L. S100 protein subcellular localization during epidermal differentiation and psoriasis. J. Histochem. Cytochem. 51, 675–685 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Foell, D. et al. Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease. J. Pathol. 216, 183–192 (2008).

    CAS  Article  Google Scholar 

  12. 12

    Ehrchen, J.M., Sunderkötter, C., Foell, D., Vogl, T. & Roth, J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity and cancer. J. Leukoc. Biol. 86, 557–566 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Vogl, T. et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat. Med. 13, 1042–1049 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Viemann, D. et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood 105, 2955–2962 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Zenz, R. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369–375 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Manitz, M.P. et al. Loss of S100A9 (MRP14) results in reduced interleukin-8–induced CD11b surface expression, a polarized microfilament system and diminished responsiveness to chemoattractants in vitro. Mol. Cell. Biol. 23, 1034–1043 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nat. Med. 13, 139–145 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Lee, H.J. & Sinha, A.A. Cutaneous lupus erythematosus: understanding of clinical features, genetic basis and pathobiology of disease guides therapeutic strategies. Autoimmunity 39, 433–444 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Caproni, M. et al. The CD40/CD40 ligand system in the skin of patients with subacute cutaneous lupus erythematosus. J. Rheumatol. 34, 2412–2416 (2007).

    PubMed  Google Scholar 

  21. 21

    Boyd, J.H., Kan, B., Roberts, H., Wang, Y. & Walley, K.R. S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products. Circ. Res. 102, 1239–1246 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells. Nat. Immunol. 9, 1297–1306 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Bogumil, T., Rieckmann, P., Kubuschok, B., Felgenhauer, K. & Brück, W. Serum levels of macrophage-derived protein MRP-8/14 are elevated in active multiple sclerosis. Neurosci. Lett. 247, 195–197 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Nukui, T. et al. S100A8/A9, a key mediator for positive feedback growth stimulation of normal human keratinocytes. J. Cell Biochem. 104, 453–464 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Tajima, M. et al. IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17–producing CD8+ T cells. J. Exp. Med. 205, 1019–1027 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Loser, K. et al. In vitro–generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Gene Ther. 12, 1294–1304 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Loser, K. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat. Med. 12, 1372–1379 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Gunzer, M., Weishaupt, C., Planelles, L. & Grabbe, S. Two-step negative enrichment of CD4+ and CD8+ T cells from murine spleen via nylon wool adherence and an optimized antibody cocktail. J. Immunol. Methods 258, 55–63 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Stutte, S., Jux, B., Esser, C. & Förster, I. CD24a expression levels discriminate Langerhans cells from dermal dendritic cells in murine skin lymph nodes. J. Invest. Dermatol. 128, 1470–1475 (2008).

    CAS  Article  Google Scholar 

Download references


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.

Author information




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.

Corresponding author

Correspondence to Karin Loser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Data, Supplementary Methods and Supplementary Figures 1 and 2 (PDF 667 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing