The Role of Foxp3+ Regulatory T Cells in Liver Transplant Tolerance
ABSTRACT The liver has long been considered a tolerogenic organ that favors the induction of peripheral tolerance. The mechanisms underlying liver tolerogenicity remain largely undefined. In this study, we characterized Foxp3-expressing CD4+CD25+ regulatory T cells (Treg) in liver allograft recipients and examined the role of Treg in inherent liver tolerogenicity by employing the mouse spontaneous liver transplant tolerance model. Orthotopic liver transplantation was performed from C57BL/10 (H2b) to C3H/HeJ (H2k) mice. The percentage of CD4+CD25+ Treg was expanded in the liver grafts and recipient spleens from day 5 up to day 100 posttransplantation, associated with high intracellular Foxp3 and CTLA4 expression. Immunohistochemistry further demonstrated significant numbers of Foxp3+ cells in the liver grafts and recipient spleens and increased transforming growth factor β expression in the recipient spleens throughout the time courses. Adoptive transfer of spleen cells from the long-term liver allograft survivors significantly prolonged donor heart graft survival. Depletion of recipient CD4+CD25+ Treg using anti-CD25 monoclonal antibody (250 μg/d) induced acute liver allograft rejection, associated with elevated anti-donor T-cell proliferative responses, CTL and natural killer activities, enhanced interleukin (IL)-2, interferon-γ, IL-10, and decreased IL-4 production, and decreased T-cell apoptotic activity in anti-CD25-treated recipients. Moreover, CTLA4 blockade by anti-CTLA4 monoclonal antibody administration exacerbated liver graft rejection when combined with anti-CD25 monoclonal antibody. Thus, Foxp3+CD4+CD25+ Treg appear to underpin spontaneous acceptance of major histocompatability complex– mismatched liver allografts in mice. CTLA4, IL-4, and apoptosis of alloreactive T cells appear to contribute to the function of Treg and regulation of graft outcome.
SourceAvailable from: Myung-Gyu Kim[Show abstract] [Hide abstract]
ABSTRACT: Recent reports suggest the presence of heat-shock protein (HSP)-reactive T cells with a regulatory phenotype in various inflammatory diseases. To test whether HSP exerts renoprotective effects through regulatory T cells (Tregs), ischemia/reperfusion injury was done with or without heat preconditioning in mice. Splenocytes from heat-preconditioned mice had Treg expansion and a reduced proliferative response upon mitogenic stimulus. T cells from heat-preconditioned mice failed to reconstitute postischemic injury when adoptively transferred to T cell-deficient nu/nu mice in contrast to those from control mice. Tregs were also increased in heat-preconditioned ischemic kidneys. Depleting Tregs before heat preconditioning abolished the renoprotective effect, while adoptive transfer of these cells back into Treg-depleted mice partially restored the beneficial effect of heat preconditioning. Inhibition of HSP70 by quercetin suppressed Treg expansion, as well as renoprotective effects. Transferring Tregs in quercetin-treated heat-preconditioned mice partially restored the beneficial effect of heat preconditioning. The specificity of immune cell HSP70 in renoprotection was confirmed by partial restoration of kidney injury when T cells from HSP70-deficient heat preconditioned mice were adoptively transferred to nu/nu mice. Thus, the renoprotective effect of HSP70 may be partially mediated by a direct immunomodulatory effect through Tregs. Better understanding of immunomodulatory mechanisms of various stress proteins might facilitate discovery of new preventive strategies in acute kidney injury.Kidney International advance online publication, 24 July 2013; doi:10.1038/ki.2013.277.Kidney International 07/2013; 85(1). DOI:10.1038/ki.2013.277 · 8.52 Impact Factor
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ABSTRACT: This study aims to investigate the effects of anti-CD25 monoclonal antibody (mAb) on the effector T cells (Teff) and CD4+CD25+ regulatory T cells (CD4+CD25+Treg) in corneal allograft rejection. Wistar rats were used as donors and SD rats were used as recipients. Routine penetrating keratoplasty (PKP) was performed. 90 SD rats were randomly divided into 5 groups: A -E. Group A (n = 6) was normal group and rats in Groups B (n = 24), C (n = 18), D (n = 18) and E (n = 24) were transplanted and subconjunctivally treated with normal saline, 100 µg anti-CD25 mAb, 100 µg anti-CD25 mAb plus 50 µg dexamethasone and 100 µg dexamethasone, respectively, on day 0, 2, 4, 6 and 8 following transplantation. The average transplant survival time in the Group B was significantly shorter than that of Groups C, D and E (P < 0.05). The mRNA expression of IFN-γ, CD25 or FOXP3 was not detected in the Group A. Compared to the Groups C, D and E, the mRNA expression of IFN-γ and CD25 in the grafts of Group B was markedly increased (P < 0.05) on day 11 following PKP. Compared with the Groups D and E, the mRNA expression of FOXP3 in the grafts of Group C was markedly decreased (P < 0.05). When compared with Group B, the mean IFN-γ level in the aqueous humour was remarkably decreased in Groups C, D and E (P < 0.05) on day 6 and 11 following PKP 11 days after PKP, the mean IFN-γ level in the aqueous humour of Groups D and E was profoundly decreased compared to the Group C (P < 0.05). No significant difference was observed in Groups D and E. But high-dose dexamethasone monotherapy have a high risk of side effects. The results suggest Teff and CD4+CD25+Treg play important roles in the corneal allograft rejection.
Article: Immune tolerance in liver disease[Show abstract] [Hide abstract]
ABSTRACT: Liver Tolerance is manifest as a bias towards immune unresponsiveness, both in the context of a Major Histocompatibility Complex-mismatched liver transplant and in the context of liver infection. Two broad classes of mechanisms account for liver tolerance. The presentation of antigens by different liver cell types results in incomplete activation of CD8+ T cells, usually leading to initial proliferation followed by either clonal exhaustion or premature death of the T cell. Many liver infections result in relatively poor CD4+ T cell activation, which may be because liver antigen-presenting cells express a variety of inhibitory cytokines and co-inhibitors ligands. Poor CD4+ T cell activation by liver antigens likely contributes to the abortive activation, exhaustion and early death of the CD8+ T cells. In addition, a network of active immunosuppressive pathways in the liver is mediated mostly by myeloid cells. Kupffer cells, myeloid-derived suppressor cells and liver dendritic cells both promote the activation of regulatory T cells, and suppress CD8+ and CD4+ effector T cells. This suppressive network responds to diverse inputs, including signals from hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells. While liver tolerance may be exploited by pathogens, it serves a valuable purpose. Hepatitis A and B infections occasionally elicit a powerful immune response sufficient to cause fatal massive liver necrosis. More commonly, the mechanisms of liver tolerance limit the magnitude of intra-hepatic immune responses, allowing the liver to recover. The cost of this adaptive mechanism may be incomplete pathogen eradication, leading to chronic infection. (Hepatology 2014;).Hepatology 12/2014; 60(6). DOI:10.1002/hep.27254 · 11.19 Impact Factor