Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice

Jeanette E. Villanueva, Stacey Nicole Walters, Mitsuru Saito, Elisabeth K. Malle, Nathan W Zammit, Katherine A. Watson, Robert Brink, Nicole L. La Gruta, Stephen I Alexander, Shane T. Grey

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)679-689
Number of pages11
Issue number4
Publication statusPublished - 1 Apr 2017


  • Allograft
  • Effector function
  • Immunosuppression
  • Islet
  • T cell
  • TRAF2

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