Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps–SHP-2 pathway

Nature Immunology volume 13, pages 551–559 (2012)Cite this article

Subjects

This article has been updated

Abstract

The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps–SHP-2 pathway and control TLR-triggered innate inflammatory responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MHC class I–deficient mice are more susceptible to TLR challenge.
Figure 2: MHC class I–deficient mice are more susceptible to infection with E. coli but are more resistant to infection with L. monocytogenes (LM).
Figure 3: MHC class I reverse signaling inhibits TLR-triggered production of proinflammatory cytokines and type I interferon in macrophages.
Figure 4: CD8+ T cells suppress TLR-triggered production of inflammatory cytokines in macrophages in an MHC class I–dependent manner.
Figure 5: MHC class I reverse signaling impairs TLR pathways in macrophages.
Figure 6: Membrane MHC class I molecules interact directly with Fps.
Figure 7: MHC class I molecules suppress TLR-triggered response by maintaining Fps activation.
Figure 8: Binding of SHP-2 to Fps and enhanced activation of SHP-2 are required for negative regulation of TLR responses by MHC class I molecules.

Similar content being viewed by others

Change history

  • 04 May 2012

    In the version of this article initially published online, some labels in Figs. 3b and 7c were incorrect and the legend for Fig. 7c incorrectly identified the siRNA used. In Fig. 3b, the label 'siRNA:' (to identify the siRNA used) should be in the left margin adjacent to 'Ctrl'; the label 'MHCI' (to identify the protein detected) should be in the left margin below that. For Fig. 7c, the label above the right lane should read 'Fps'; its accompanying legend should end "...control or Fps-specific siRNA." The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O'Neill, L.A. & Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Antoniou, A.N., Powis, S.J. & Elliott, T. Assembly and export of MHC class I peptide ligands. Curr. Opin. Immunol. 15, 75–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Raulet, D.H. MHC class I-deficient mice. Adv. Immunol. 55, 381–421 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Orr, M.T. & Lanier, L.L. Natural killer cell education and tolerance. Cell 142, 847–856 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jonsson, A.H. & Yokoyama, W.M. Natural killer cell tolerance licensing and other mechanisms. Adv. Immunol. 101, 27–79 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Elliott, J.M., Wahle, J.A. & Yokoyama, W.M. MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J. Exp. Med. 207, 2073–2079 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tscherning, T. & Claesson, M.H. Signal transduction via MHC class-I molecules in T cells. Scand. J. Immunol. 39, 117–121 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Skov, S. lntracellular signal transduction mediated by ligation of MHC class I molecules. Tissue Antigens 51, 215–223 (1998).

    CAS  PubMed  Google Scholar 

  13. Pedersen, A.E., Skov, S., Bregenholt, S., Ruhwald, M. & Claesson, M.H. Signal transduction by the major histocompatibility complex class I molecule. APMIS 107, 887–895 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Yang, J. et al. Targeting β2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell 10, 295–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, X., Rozengurt, E. & Reed, E.F. HLA class I molecules partner with integrin β4 to stimulate endothelial cell proliferation and migration. Sci. Signal. 3, ra85 (2010).

    CAS  PubMed  Google Scholar 

  16. Rubio, G. et al. Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines. J. Leukoc. Biol. 76, 116–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Skov, S., Odum, N. & Claesson, M.H. MHC class I signaling in T cells leads to tyrosine kinase activity and PLC-γ1 phosphorylation. J. Immunol. 154, 1167–1176 (1995).

    CAS  PubMed  Google Scholar 

  18. Pedersen, A.E., Bregenholt, S., Skov, S., Vrang, M.L. & Claesson, M.H. Protein tyrosine kinases p53/56lyn and p72syk in MHC class I-mediated signal transduction in B lymphoma cells. Exp. Cell Res. 240, 144–150 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, X. et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat. Immunol. 12, 416–424 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, J.C. & Lanier, L.L. Cutting edge: viral infection breaks NK cell tolerance to “missing self”. J. Immunol. 181, 7453–7457 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Perona-Wright, G. et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe 6, 503–512 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zirngibl, R.A., Senis, Y. & Greer, P.A. Enhanced endotoxin sensitivity in fps/fes-null mice with minimal defects in hematopoietic homeostasis. Mol. Cell. Biol. 22, 2472–2486 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Santos, S.G., Powis, S.J. & Arosa, F.A. Misfolding of major histocompatibility complex class I molecules in activated T cells allows cis-interactions with receptors and signaling molecules and is associated with tyrosine phosphorylation. J. Biol. Chem. 279, 53062–53070 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Udell, C.M., Samayawardhena, L.A., Kawakami, Y., Kawakami, T. & Craig, A.W. Fer and Fps/Fes participate in a Lyn-dependent pathway from FcɛRI to platelet-endothelial cell adhesion molecule 1 to limit mast cell activation. J. Biol. Chem. 281, 20949–20957 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Rui, Y. et al. PECAM-1 ligation negatively regulates TLR4 signaling in macrophages. J. Immunol. 179, 7344–7351 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. An, H. et al. SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 25, 919–928 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Sun, M. & Fink, P.J. A new class of reverse signaling costimulators belongs to the TNF family. J. Immunol. 179, 4307–4312 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Greenwald, R.J., Freeman, G.J. & Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).

    Article  PubMed  Google Scholar 

  30. Chen, L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 4, 336–347 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Kim, K.D. et al. Adaptive immune cells temper initial innate responses. Nat. Med. 13, 1248–1252 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Zimmer, J. et al. Clinical and immunological aspects of HLA class I deficiency. QJM 98, 719–727 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Gadola, S.D., Moins-Teisserenc, H.T., Trowsdale, J., Gross, W.L. & Cerundolo, V. TAP deficiency syndrome. Clin. Exp. Immunol. 121, 173–178 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Colonna, M. et al. Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J. Immunol. 160, 3096–3100 (1998).

    CAS  PubMed  Google Scholar 

  35. Arosa, F.A., Santos, S.G. & Powis, S.J. Open conformers: the hidden face of MHC-I molecules. Trends Immunol. 28, 115–123 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Little, A.M., Nossner, E. & Parham, P. Dissociation of β2-microglobulin from HLA class I heavy chains correlates with acquisition of epitopes in the cytoplasmic tail. J. Immunol. 154, 5205–5215 (1995).

    CAS  PubMed  Google Scholar 

  37. Izuhara, K., Feldman, R.A., Greer, P. & Harada, N. Interaction of the c-fes proto-oncogene product with the interleukin-4 receptor. J. Biol. Chem. 269, 18623–18629 (1994).

    CAS  PubMed  Google Scholar 

  38. Matsuda, T. et al. Activation of Fes tyrosine kinase by gp130, an interleukin-6 family cytokine signal transducer, and their association. J. Biol. Chem. 270, 11037–11039 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Brizzi, M.F. et al. Granulocyte-macrophage colony-stimulating factor stimulates JAK2 signaling pathway and rapidly activates p93fes, STAT1 p91, and STAT3 p92 in polymorphonuclear leukocytes. J. Biol. Chem. 271, 3562–3567 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Filippakopoulos, P. et al. Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell 134, 793–803 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hellwig, S. & Smithgall, T.E. Structure and regulation of the c-Fes protein-tyrosine kinase. Front. Biosci. 17, 3146–3155 (2011).

    Article  Google Scholar 

  42. Greer, P. Closing in on the biological functions of Fps/Fes and Fer. Nat. Rev. Mol. Cell Biol. 3, 278–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Lorenz, U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Parsons, S.A. & Greer, P.A. The Fps/Fes kinase regulates the inflammatory response to endotoxin through down-regulation of TLR4, NF-κB activation, and TNF-α secretion in macrophages. J. Leukoc. Biol. 80, 1522–1528 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Xu, S. et al. IL-17A-producing γδT cells promote CTL responses against Listeria monocytogenes infection by enhancing dendritic cell cross-presentation. J. Immunol. 185, 5879–5887 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank G. Feng (University of California, San Diego) for mice with loxP-flanked alleles encoding SHP-2; H. Shen (University of Pennsylvania School of Medicine) for L. monocytogenes; N. van Rooijen (Free University of Amsterdam) for liposomes; J. Long, X. Zuo and P. Ma for technical assistance; and T. Chen and Y. Han for discussions. Supported by the National Key Basic Research Program of China (2012CB910202 and 2010CB911903), the National 125 Key Project (2012ZX10002-014 and 2012AA020901), the National Natural Science Foundation of China (81123006) and the Shanghai Committee of Science and Technology (10DZ1910300).

Author information

Author notes

  1. Sheng Xu and Xingguang Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Sheng Xu, Xingguang Liu, Yan Bao, Xuhui Zhu, Chaofeng Han, Peng Zhang & Xuetao Cao

  2. National Center of Biomedical Analysis, Beijing, China

    Xuemin Zhang & Weihua Li

  3. National Key Laboratory of Molecular Biology, Chinese Academy of Medical Sciences, Beijing, China

    Xuetao Cao

Authors
  1. Sheng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xingguang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuhui Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chaofeng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuemin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weihua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuetao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.C. and S.X. designed the experiments; S.X., X.L., Y.B., C.H., X.Zhu, P.Z., W.L. and X.Zha. did the experiments; X.C., S.X. and X.L. analyzed data and wrote the paper; and X.C. was responsible for research supervision, coordination and strategy.

Corresponding author

Correspondence to Xuetao Cao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 869 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, S., Liu, X., Bao, Y. et al. Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps–SHP-2 pathway. Nat Immunol 13, 551–559 (2012). https://doi.org/10.1038/ni.2283

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2283

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing