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https://hdl.handle.net/2440/121090
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Type: | Journal article |
Title: | Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice |
Author: | Villanueva, J.E. Walters, S.N. Saito, M. Malle, E.K. Zammit, N.W. Watson, K.A. Brink, R. La Gruta, N.L. Alexander, S.I. Grey, S.T. |
Citation: | Diabetologia, 2017; 60(4):679-689 |
Publisher: | Springer Nature |
Issue Date: | 2017 |
ISSN: | 0012-186X 1432-0428 |
Statement of Responsibility: | Jeanette E. Villanueva, Stacey N. Walters, Mitsuru Saito, Elisabeth K. Malle, Nathan W. Zammit, Katherine A. Watson, Robert Brink, Nicole L. La Gruta, Stephen I. Alexander, Shane T. Grey |
Abstract: | Aims/Hypothesis: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was associated with thromboembolic complications. Targeting downstream intracellular components shared between CD40 and other TNF family co-stimulatory molecules could bypass these complications. TNF receptor associated factor 2 (TRAF2) integrates multiple TNF receptor family signalling pathways that are critical for T cell activation and may be a central node of alloimmune responses. Methods: T cell-specific Traf2-deficient mice (Traf2TKO) were generated to define the role of TRAF2 in CD4⁺ T cell effector responses that mediate islet allograft rejection in vivo. In vitro allograft responses were tested using mixed lymphocyte reactions and analysis of IFN-γ and granzyme B effector molecule expression. T cell function was assessed using anti-CD3/CD28-mediated proliferation and T cell polarisation studies. Results: Traf2TKO mice exhibited permanent survival of full MHC-mismatched pancreatic islet allografts without exogenous immunosuppression. Traf2TKO CD4⁺ T cells exhibited reduced proliferation, activation and acquisition of effector function following T cell receptor stimulation; however, both Traf2TKO CD4⁺ and CD8⁺ T cells exhibited impaired alloantigen-mediated proliferation and acquisition of effector function. In polarisation studies, Traf2TKO CD4⁺ T cells preferentially converted to a T helper (Th)2 phenotype, but exhibited impaired Th17 differentiation. Without TRAF2, thymocytes exhibited dysregulated TNF-mediated induction of c-Jun N-terminal kinase (JNK) and canonical NFκB pathways. Critically, targeting TRAF2 in T cells did not impair the acute phase of CD8-dependent viral immunity. These data highlight a specific requirement for a TRAF2-NFκB and TRAF2-JNK signalling cascade in T cell activation and effector function in rejecting islet allografts. Conclusion/Interpretation: Targeting TRAF2 may be useful as a therapeutic approach for immunosuppression-free islet allograft survival that avoids the thromboembolic complications associated with the use of anti-CD40L antibodies. |
Keywords: | Allograft; effector function; immunosuppression; islet; Tcell; TRAF2 |
Rights: | © Springer-Verlag Berlin Heidelberg 2017 |
DOI: | 10.1007/s00125-016-4198-7 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/427695 http://purl.org/au-research/grants/arc/201302657 http://purl.org/au-research/grants/nhmrc/1071916 http://purl.org/au-research/grants/nhmrc/569825 |
Published version: | http://dx.doi.org/10.1007/s00125-016-4198-7 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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