title: Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus.
abstract: 4-1BB ligand (4-1BBL) is a member of the TNF family expressed on activated APC. 4-1BBL binds to 4-1BB (CD137) on activated CD4 and CD8 T cells and in conjunction with strong signals through the TCR provides a CD28-independent costimulatory signal leading to high level IL-2 production by primary resting T cells. Here we report the immunological characterization of mice lacking 4-1BBL and of mice lacking both 4-1BBL and CD28. 4-1BBL-/- mice mount neutralizing IgM and IgG responses to vesicular stomatitis virus that are indistinguishable from those of wild-type mice. 4-1BBL-/- mice show unimpaired CTL responses to lymphocytic choriomeningitis virus (LCMV) and exhibit normal skin allograft rejection but have a weaker CTL response to influenza virus than wild-type mice. 4-1BBL-/-CD28-/- mice retain the CTL response to LCMV, respond poorly to influenza virus, and exhibit a delay in skin allograft rejection. In agreement with these in vivo results, allogeneic CTL responses of CD28-/- but not CD28+/+ T cells to 4-1BBL-expressing APC are substantially inhibited by soluble 4-1BB receptor as is the in vitro secondary response of CD28+ T cells to influenza virus peptides. TCR-transgenic CD28-/- LCMV glycoprotein-specific T cells are insensitive to the presence of 4-1BBL when a wild-type peptide is used, but the response to a weak agonist peptide is greatly augmented by the presence of 4-1BBL. These results further substantiate the idea that different immune responses vary in their dependence on costimulation and suggest a role for 4-1BBL in augmenting suboptimal CTL responses in vivo.
authors.affiliation: Department of Immunology, University of Toronto, Ontario, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: DeBenedette
authors.forename: T
authors.initials: T
authors.lastname: Wen
authors.forename: M F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: B H
authors.initials: BH
authors.lastname: Barber
authors.forename: K L
authors.initials: KL
authors.lastname: Stocking
authors.forename: J J
authors.initials: JJ
authors.lastname: Peschon
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D018106:CD28 Antigens / Q000235:genetics* / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D005260:Female; D018390:Gene Targeting; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D008024:Ligands; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000914:Antibodies, Viral; D018106:CD28 Antigens; D008024:Ligands; C505975:Tnfsf9 protein, mouse; D014409:Tumor Necrosis Factor-alpha