title: Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.|Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Villanueva
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Walters
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, University of Sydney, Westmead, NSW, Australia.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Malle
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Zammit
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia.|Immunology Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC, Australia.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Watson
authors.affiliation: B Cell Biology Group, Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia.|Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, University of Sydney, Westmead, NSW, Australia.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. s.grey@garvan.org.au.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D047992:TNF Receptor-Associated Factor 2; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Allograft; Effector function; Immunosuppression; Islet; T cell; TRAF2