Elsevier

Transplantation Proceedings

Volume 41, Issue 1, January–February 2009, Pages 233-235
Transplantation Proceedings

Liver transplantation
Outcome
γδT Cells Are Involved in Liver Transplant Tolerance

https://doi.org/10.1016/j.transproceed.2008.10.040Get rights and content

Abstract

The role of nonconventional T cells in innate and adaptive immunity is just emerging; γδT cells play important roles in anti-tumor and anti-infectious diseases. The involvement of γδT cells in immunologic responses to hematopoietic cell transplantation remains controversial; divergent results have been reported depending on the murine strains and model systems. Whether γδT cells are involved in solid organ transplantation is understudied. We have characterized the γδT cells in mouse livers and spleens to evaluate their contributions to liver transplant tolerance posttransplantation using a murine allogeneic liver transplant model which induces spontaneous T regulatory cell (Treg)-dependent tolerance. Our studies revealed that γδT cells comprised about 20% of the population of liver nonparenchymal cells (NPCs). In naïve C3H mice they were CD4, CD8, and NK1.1 negative. The percentage of γδT cells decreased in spontaneously tolerated liver grafts posttransplantation from 20% in naïve C3H livers to <10% in allografts throughout the time course. In contrast, they increased in liver grafts with rejection induced by anti-CTLA4 plus anti-CD25 mAb administration. CD4 and CD8 expression on γδT cells dramatically increased in the tolerated but not rejected livers posttransplantation to >20% of CD4+ and 30% of CD8+. Our results suggested that γδT cells are involved in allogeneic immune responses. Whether γδT cells function as the causal or the effector cells in allograft tolerance rejection warrants further investigation.

Section snippets

Materials and Methods

Male C57BL/10 (B10; H2b) and C3H/HeJ (C3H; H2k) mice purchased from Jackson Laboratory (Bar Harbor, Maine, United States) were housed in a specific pathogen-free facility under a protocol approved by the Institutional Animal Care and Use Committee. Orthotopic liver transplantation (OLT) was performed from B10 to C3H mice as previously described.8, 9 Cohorts of animals received either anti-CTLA4 mAb (UC10-4F10-11; Chimerigen, Allston, Mass, United States; 250 μg/mouse, days 0, 2, 4, IP) or

Results

Liver grafts from B10 donors were spontaneously accepted by C3H recipients without immunosuppression. Compared with control IgG-treated recipients (mean survival time [MST] >100 days), liver grafts were acutely rejected by recipients that received anti-CD25 mAb either pre- (MST 14.9 ± 9.8 days; n = 8; P < .01) or posttransplantation (MST 16.8 ± 12.6 days; n = 6; P < .01) or anti-CTLA4 mAb (MST 8.5 ± 3.6 days; n = 6), or combined treatment (MST 7.8 ± 1.6 days; n = 5; P < .01). In naïve C3H mice,

Discussion

While the contribution of circulating and tissue-specific γδT cells is firmly established in a wide variety of innate mechanisms,1, 2, 3 their roles in adaptive and autoimmune responses continue to emerge.3, 10 The contribution of γδT cells to solid organ transplantation immunology has not been studied extensively: the presence of γδT cells in the blood of transplant patients has been associated with stable liver or kidney allograft function.5, 6 A preponderance of Vδ1 γδT cells was associated

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  • Characteristics of Vδ1<sup>+</sup> and Vδ2<sup>+</sup> γδ T cell subsets in acute liver allograft rejection

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    Vδ1+ γδ T cells, predominant in tissue such as that in the spleen, intestine, and liver, possess regulatory and effector properties; Vδ2+ γδ T cells, which are the main subset of γδ T cells in the peripheral blood, possess defense properties against pathogens [15]. An animal study showed that the total percentage of γδ T cells decreased in a spontaneously tolerated liver graft, and increased in a liver allograft rejected after anti-CTLA4 or anti-CD25 monoclonal antibody administration [14]. In humans, γδ T cells have been reported to be involved in renal allograft rejection; γδ T cells also participate in cardiac allograft acceptance [16,17].

  • Regulatory functions of γδ T cells

    2013, International Immunopharmacology
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    In this context, liver transplantation is of special interest as operational tolerance (i.e. a status where immunosuppressive therapy can be weaned) is observed in 15 to 20% of liver allograft recipients. In a mouse model of allogeneic liver transplantation, Malone and co-workers observed a significantly reduced proportion of intrahepatic γδ T cells in spontaneously tolerated liver grafts, whereas intrahepatic γδ T cell numbers increased when organ rejection was induced [56]. While these studies suggest that γδ T cells might contribute to allograft rejection, other observations point to a regulatory function of γδ T cells in organ transplantation.

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This work was supported by funding from the Division of Transplantation, Department of Surgery, and the Provost Bridge Fund of the University of Washington, Seattle, Washington, USA.

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