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

• Published in: The Journal of immunology (1950) 1999-11, Vol.163 (9), p.4833-4841
• Main Authors: DeBenedette, Mark A, Wen, Tao, Bachmann, Martin F, Ohashi, Pamela S, Barber, Brian H, Stocking, Kim L, Peschon, Jacques J, Watts, Tania H
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand; Animals; Antibodies, Viral - biosynthesis; CD28 Antigens - genetics; CD28 Antigens - physiology; Cytotoxicity, Immunologic - genetics; Female; Gene Targeting; Graft Rejection - genetics; Graft Rejection - immunology; Influenza A virus - immunology; Influenza virus; Ligands; Lymphocytic choriomeningitis virus - immunology; Male; Mice; Mice, Inbred A; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Skin Transplantation - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - deficiency; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology; Vesicular stomatitis Indiana virus - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.9.4833

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.