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.

  • Correspondence
  • Published:

Ag-specific CD4 T cells promote innate immune responses in liver ischemia reperfusion injury

Cellular & Molecular Immunology volume 16, pages 98–100 (2019)Cite this article

Our previous studies have documented the unique enrichment of activated CD4 T cells in the liver. Blocking de novo T cell activation did not interfere with their function in ischemia reperfusion injury (IRI).1 We also demonstrated that the CD154-CD40 pathway, but not IFN-γ, was critical for IRI in the liver. Interestingly, alloimmune-primed hosts had significantly more severe IRI in their own livers, which was mediated mainly by CD4 T cells.2 These data prompted us to propose that pre-existing activated CD4 T cells in a host participate in the liver innate immune response against IRI. However, whether these activated/memory T cells require Ag stimulation to function in liver IRI remains unclear. In this report, we addressed this question by utilizing OT II (RAG −/−) T cell receptor transgenic CD4 T cells in a murine liver IRI model.

The current series of experiments provided the first direct evidence that only activated/memory T cells are capable of promoting the liver innate immune response in an Ag-independent and CD154-dependent manner. Combined with our previous studies,1 IR-triggered TLR4 upregulates CD40 on KCs, which then engages CD154 on activated/memory CD4 T cells, leading to reversed co-stimulatory signaling in KCs. Activation of both TLR and CD40 is required for full-scale activation of the liver inflammatory immune response against IRI.

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

Relevant articles

Open Access articles citing this article.

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

Fig. 1

References

  1. Shen, X. et al. CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury. Hepatology 50, 1537–1546 (2009).

    Article  CAS  Google Scholar 

  2. Shen, X. et al. Alloimmune activation enhances innate tissue inflammation/injury in a mouse model of liver ischemia/reperfusion injury. Am. J. Transplant. 10, 1729–1737 (2010).

    Article  CAS  Google Scholar 

  3. Janelsins, B. M., Lu, M. & Datta, S. K. Altered inactivation of commensal LPS due to acyloxyacyl hydrolase deficiency in colonic dendritic cells impairs mucosal Th17 immunity. Proc. Natl Acad. Sci. USA 111, 373–378 (2014).

    Article  CAS  Google Scholar 

  4. Abe, T. et al. Kupffer cell-derived interleukin 10 is responsible for impaired bacterial clearance in bile duct-ligated mice. Hepatology 40, 414–423 (2004).

    Article  CAS  Google Scholar 

  5. Zhang, M., Xu, S., Han, Y. & Cao, X. Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β. Hepatology 53, 306–316 (2011).

    Article  CAS  Google Scholar 

  6. Kinsey, G. et al. Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection. J. Am. Soc. Nephrol. 23, 1528–1537 (2012).

    Article  CAS  Google Scholar 

  7. Thangavelu, G., Gill, R., Boon, L., Ellestad, K. & Anderson, C. Control of in vivo collateral damage generated by T cell immunity. J. Immunol. 191, 1686–1691 (2013).

    Article  CAS  Google Scholar 

  8. Zhai, Y. et al. Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion. Hepatology 47, 199–206 (2008).

    Article  CAS  Google Scholar 

  9. Singer, B. D., King, L. S. & D’Alessio, F. R. Regulatory T cells as immunotherapy. Front. Immunol. 5, 46 (2014).

    Article  Google Scholar 

  10. Ma, Z., Zhang, E., Yang, D. & Lu, M. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell Mol. Immunol. 12, 273–282 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Six talent peaks project in Jiangsu Province​ (WSW-019).

Author information

Authors and Affiliations

  1. Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Jianhua Rao, Feng Cheng, Shikun Yang, Yuan Zhai & Ling Lu

  2. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA

    Jianhua Rao & Yuan Zhai

Authors
  1. Jianhua Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shikun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ling Lu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rao, J., Cheng, F., Yang, S. et al. Ag-specific CD4 T cells promote innate immune responses in liver ischemia reperfusion injury. Cell Mol Immunol 16, 98–100 (2019). https://doi.org/10.1038/s41423-018-0051-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-018-0051-x

This article is cited by

Search

Advanced search

Quick links