Skip to main content
SpringerLink
Log in

Decreased PD-1/PD-L1 Expression Is Associated with the Reduction in Mucosal Immunoglobulin A in Mice with Intestinal Ischemia Reperfusion

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Intestinal ischemia/reperfusion (I/R) disrupts intestinal mucosal integrity and immunoglobulin A (IgA) generation. It has recently been shown that the programmed cell death-1 receptor (PD-1) plays a crucial role in regulating intestinal secreted IgA (sIgA).

Aims

To evaluate changes in PD-1 and PD-ligand 1 (PD-L1) expression on Peyer’s patches (PP) CD4+ T cells and to investigate the correlation between PD-1/PD-L1 and intestinal IgA production/mucosal integrity in mice following intestinal I/R.

Methods

I/R injury was induced by clamping the superior mesenteric artery for 1 h followed by 2-h reperfusion. PD-1/PD-L1 expression on PP CD4+ T cells was measured in I/R and sham-operated mice. Additionally, transforming growth factor-β1 (TGF-β1) and interleukin-21 (IL-21) mRNA in CD4+ T cells and IgA+ and IgM+ in PP B cells, as well as intestinal mucosal injury and sIgA levels, were assessed.

Results

PD-1/PD-L1, TGF-β1, and IL-21 expression was down-regulated after intestinal I/R. Furthermore, IgA+ B cells decreased and IgM+ B cells increased in mice with intestinal I/R. Importantly, decreased PD-1/PD-L1 expression was correlated with increased mucosal injury and decreased IgA levels, as well as with decreased TGF-β1 and IL-21 expression.

Conclusions

Intestinal I/R inhibits PD-1/PD-L1 expression on PP CD4+ T cells, which was associated with an impaired intestinal immune system and mechanical barriers. Our study indicates that PD-1/PD-L1 expression on CD4+ T cells may be involved in the pathogenesis of intestinal I/R injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mallick IH, Yang W, Winslet MC, et al. Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49:1359–1377.

    Article  CAS  PubMed  Google Scholar 

  2. Feinman R, Deitch EA, Watkins AC, et al. HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2010;299:G833–843.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Martin B. Prevention of gastrointestinal complications in the critically ill patient. AACN Adv Crit Care. 2007;18:158–166.

    Article  PubMed  Google Scholar 

  4. Zhang XY, Liu ZM, Wen SH, et al. Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 2012;116:1035–1046.

    Article  CAS  PubMed  Google Scholar 

  5. Liu KX, Li YS, Huang WQ, et al. Immediate postconditioning during reperfusion attenuates intestinal injury. Intensive Care Med. 2009;35:933–942.

    Article  PubMed  Google Scholar 

  6. Li H, Wu GH, Chen J. Effect of glucagon-like peptide 2 on the intestinal mucosal immunity and correlative cytokines in mice with gut ischemia/reperfusion injury. Zhonghua Wei Chang Wai Ke Za Zhi. 2006;9:67–70.

    PubMed  Google Scholar 

  7. Fukatsu K, Sakamoto S, Hara E, et al. Gut ischemia-reperfusion affects gut mucosal immunity: a possible mechanism for infectious complications after severe surgical insults. Crit Care Med. 2006;34:182–187.

    Article  PubMed  Google Scholar 

  8. Yoshiya K, Lapchak PH, Thai TH, et al. Depletion of gut commensal bacteria attenuates intestinal ischemia/reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2011;301:G1020–1030.

    Article  CAS  PubMed  Google Scholar 

  9. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12:821–832.

    Article  CAS  PubMed  Google Scholar 

  10. Fagarasan S, Kawamoto S, Kanagawa O, et al. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol. 2010;28:243–273.

    Article  CAS  PubMed  Google Scholar 

  11. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–772.

    Article  CAS  PubMed  Google Scholar 

  12. Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–245.

    Article  CAS  PubMed  Google Scholar 

  13. Schreiner B, Mitsdoerffer M, Kieseier BC, et al. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PDL1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol. 2004;155:172–182.

    Article  CAS  PubMed  Google Scholar 

  14. Esch KJ, Juelsgaard R, Martinez PA, et al. Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. J Immunol. 2013;191:5542–5550.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Simone R, Piatti G, Saverino D. The inhibitory co-receptors: a way to save from anergy the HIV-specific T cells. Curr HIV Res. 2009;7:266–272.

    Article  CAS  PubMed  Google Scholar 

  16. Kawamoto S, Tran TH, Maruya M, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012;336:485–489.

    Article  CAS  PubMed  Google Scholar 

  17. Chiu CJ, McArdle AH, Brown R, et al. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 1970;101:478–483.

    Article  CAS  PubMed  Google Scholar 

  18. Seo GY, Youn J, Kim PH. IL-21 ensures TGF-beta 1-induced IgA isotype expression in mouse Peyer’s patches. J Leukoc Biol. 2009;85:744–750.

    Article  CAS  PubMed  Google Scholar 

  19. Godínez-Victoria M, Drago-Serrano ME, Reyna-Garfias H, et al. Effects on secretory IgA levels in small intestine of mice that underwent moderate exercise training followed by a bout of strenuous swimming exercise. Brain Behav Immun. 2012;26:1300–1309.

    Article  PubMed  Google Scholar 

  20. Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73:3591–3603.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Belai EB, de Oliveira CE, Gasparoto TH, et al. PD-1 blockage delays murine squamous cell carcinoma development. Carcinogenesis. 2014;35:424–431.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang Y, Zhou Y, Lou J, et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care. 2010;14:R220.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Guignant C, Lepape A, Huang X, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15:R99.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Ji H, Shen X, Gao F, et al. Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury. Hepatology. 2010;52:1380–1389.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Jaworska K, Ratajczak J, Huang L, et al. Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J Immunol. 2015;194:325–333.

    Article  CAS  PubMed  Google Scholar 

  26. Stavnezer J, Kang J. The surprising discovery that TGF beta specifically induces the IgA class switch. J Immunol. 2009;182:5–7.

    Article  CAS  PubMed  Google Scholar 

  27. Carter L, Fouser LA, Jussif J, Fitz L, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–643.

    Article  CAS  PubMed  Google Scholar 

  28. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Fagarasan S, Honjo T. Regulation of IgA synthesis at mucosal surfaces. Curr Opin Immunol. 2004;16:277–283.

    Article  CAS  PubMed  Google Scholar 

  30. Kato LM, Kawamoto S, Maruya M, et al. Gut TFH and IgA: key players for regulation of bacterial communities and immune homeostasis. Immunol Cell Biol. 2014;92:49–56.

    Article  CAS  PubMed  Google Scholar 

  31. Suzuki K, Meek B, Dous Y, et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci USA. 2004;101:1981–1986.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Fagarasan S, Muramatsu M, Suzuki K, et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science. 2002;298:1424–1427.

    Article  CAS  PubMed  Google Scholar 

  33. Phalipon A. Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells. Immunity. 2003;18:739–749.

    Article  PubMed  Google Scholar 

  34. Aytekin C, Tuygun N, Gokce S, et al. Selective IgA deficiency: clinical and laboratory features of 118 children in Turkey. J Clin Immunol. 2012;32:961–966.

    Article  CAS  PubMed  Google Scholar 

  35. Wang N, Shen N, Vyse TJ, et al. Selective IgA deficiency in autoimmune diseases. Mol Med. 2011;17:1383–1396.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Strugnell RA, Wijburg OL. The role of secretory antibodies in infection immunity. Nat Rev Microbiol. 2010;8:656–667.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Grant 81270456 and 81171847 from the National Natural Science Foundation of China (to Dr. K-X Liu), and grants S2013010015398 from the Natural Science Foundation of Guang Dong Province, China (to Dr. Xu-yu Zhang).

Conflict of interest

None.

Author information

Author notes

    Authors and Affiliations

    1. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China

      Xu-Yu Zhang, Hu-fei Zhang, Yun-Sheng Li, Shi-Hong Wen, Jian-Tong Shen & Ke-Xuan Liu

    2. Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

      Zi-Meng Liu

    Authors
    1. Xu-Yu Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zi-Meng Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Hu-fei Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yun-Sheng Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Shi-Hong Wen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jian-Tong Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ke-Xuan Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Ke-Xuan Liu.

    Additional information

    Xu-Yu Zhang and Zi-Meng Liu have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, XY., Liu, ZM., Zhang, Hf. et al. Decreased PD-1/PD-L1 Expression Is Associated with the Reduction in Mucosal Immunoglobulin A in Mice with Intestinal Ischemia Reperfusion. Dig Dis Sci 60, 2662–2669 (2015). https://doi.org/10.1007/s10620-015-3684-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10620-015-3684-y

    Keywords

    Search

    Navigation