Research Group

  • Dr Angus W. Thomson, Principal Investigator
  • Dr Zhiliang Wang, Co-Investigator
  • Dr Daisuke Tokita, Research Associate
  • Dr Giorgio Raimondi, Research Associate
  • Mr Alan Zahorchak, Research Technician
  • Dr Krystal Gerald, Collaborator
  • Dr Tina L. Sumpter, Research Associate
  • Dr Antonino Castellaneta, Research Associate

Location

  • University of Pittsburgh, Pittsburgh, USA

Title

  • Endotoxin Tolerance, Cross-tolerance and Liver Transplant Outcome

The liver is an immune organ, with a unique constituency of innate and adaptive immune cells. It displays inherent tolerogenic properties, reflected in oral tolerance, persistence of viral infections, tumor metastasis and the acceptance of MHC-mismatched liver transplants without immunosuppressive therapy in rodents and large animal models. Hepatic dendritic cells (DC) are highly-specialized, antigen-presenting cells (APCs) that may play key roles in liver transplant tolerance. In these studies, we have examined molecular regulation of the function of liver conventional myeloid DC (mDC) and non-conventional plasmacytoid DC (pDC). In particular, we have focused on mechanisms that render these important APCs resistant to maturation in response to gut-derived microbial products to which they are constantly exposed in the normal steady state. This resistance to maturation may underlie their tolerogenic properties and confer ability to subvert alloimmune responses crucial for liver graft rejection. Our novel findings suggest that the transmembrane adaptor protein DAP12 plays an important role in promoting negative regulation of liver mDC function (1, 2) and attenuation of their T cell allostimulatory activity. We have also shown that ligation of the NOD2 receptor by muramyl dipeptide, a product of gut bacteria, subverts the T cell stimulatory function of liver pDC (3). Our studies on liver pDC have also revealed a role for the emerging IL-12 family member IL-27 in their ability to regulate T cell responses (4). Our most recent work shows that expression of CD39 by murine or human liver mDC attenuates their pro-inflammatory activity and liver transplant ischemia-reperfusion injury (5).

Figure 1.

Figure 1. Generation of tolerogenic DC in the liver environment by continuous in situ exposure to LPS and regulatory cytokines. Depicted are the negative regulators of TLR responses and NFκB activation that we postulate impose a tolerogenic phenotype.

References

  • 1. Sumpter TL, Lunz JG III, Demetris AJ, Thomson AW. Molecular regulation of hepatic dendritic cell function and its relation to liver transplant outcome. Transplantation 2009;88(3 Suppl):S40.
  • 2. Sumpter TL, Packiam V, Yoshida O, et al. DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability. J Immunol 2011;186:1970.
  • 3. Castellaneta A, Sumpter TL, Chen L, et al. NOD2 ligation subverts IFNα production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via PD-L1 expression. J Immunol 2009;183:6922.
  • 4. Matta BM, Raimondi G, Sumpter TL, et al. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid DC. J Immunol 2012;188:5227.
  • 5. Yoshida O, Kimura S, Jackson E, et al. CD39 expression by hepatic myeloid dendritic cells attenuates their pro-inflammatory activity and liver transplant ischemia-reperfusion injury. Hepatology. (Manuscript submitted).

Publications

  • Thomson AW. Tolerogenic dendritic cells: all present and correct? Am J Transplant 2010;10:214.
  • Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010;10:753.
  • Tokita D, Sumpter TL, Raimondi G, et al. Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity and dependent on regulatory T cells. Transplantation 2008;86(Suppl 2S):180; (Abstract).
  • Castellaneta A, Sumpter TL, Tokita D, Thomson AW. NOD2 signaling in vivo subverts the functional response of hepatic dendritic cells to TLR4 ligation. 3rd Intl DAMPs and Alarmins Symposium. J Leukocyte Biol. 2008; 84:A13. Poster presentation, Society for Leukocyte Biology Symposium, Pittsburgh, 2008; (Abstract).
  • Sumpter TL, Thomson AW. DAP12 expression regulates maturation resistance in liver dendritic cells. Am J Transplant 2009;9(Suppl 2):475. Poster presentation, American Transplant Congress 2009; (Abstract).
  • Castellaneta A, Sumpter TL, Tokita D, Thomson AW. NOD2 signaling in vivo subverts the functional response of hepatic dendritic cells to TLR ligation. Am J Transplant 2009;9(Suppl 2):475. Poster presentation, American Transplant Congress 2009; (Abstract).
  • Sumpter TL, Thomson AW. DAP12 renders liver dendritic cells resistant to maturation. J Immunol 2009;182:91.14; (Abstract).
  • Sumpter TL, Thomson AW. DAP12 expression in liver dendritic cells controls their maturation and T cell allostimulatory capacity. Am J Transplant 2010;10(Suppl 4):95. Oral presentation, American Transplant Congress 2009; (Abstract).
  • Sumpter TL, Dangi A, Thomson AW, Gandhi S. Hepatic stellate cells affect the maturation of liver dendritic cells and undermine the induction of allogeneic CD8+ T cell responses. Am J Transplant 2011;11(Suppl 2):217. Poster presentation, American Transplant Congress 2009; (Abstract).
  • Matta BM, Raimondi G, Thomson AW. IL-27 promotes IL-10 production and B7-H1 expression by plasmacytoid DC and augments their expansion of Foxp3+ allogeneic CD4+ T cells. Am J Transplant 2011;11(Suppl 2):218. Oral presentation, American Transplant Congress 2011. Oral presentation, American Transplant Congress 2009; (Abstract).
  • Matta BM, Raimondi G, Rosborough BR, Thomson AW. IL-27 and B7-H1 mediate liver plasmacytoid DC ability to suppress delayed-type hypersensitivity responses. J Immunol 2012;188:48.9. Oral presentation, American Association for Immunologists Meeting, Boston, 2012; (Abstract).
  • Matta BM, Raimondi G, Rosborough BR,Thomson AW. IL-27 and B7-H1 mediate liver plasmacytoid DC ability to suppress delayed-type hypersensitivity responses. Am J Transplant 2012;12(Suppl 3):96. Oral presentation, American Transplant Congress, Boston, 2012; (Abstract).