4-1BB Ligand, a Member of the TNF Family, Is Important for the Generation of Antiviral CD8 T Cell Responses

• Published in: The Journal of immunology (1950) 1999-11, Vol.163 (9), p.4859-4868
• Main Authors: Tan, Joyce T, Whitmire, Jason K, Ahmed, Rafi, Pearson, Thomas C, Larsen, Christian P
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand; Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - virology; B7-1 Antigen - physiology; CD28 Antigens - physiology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Immunity, Cellular - genetics; Ligands; Lymphocyte Activation - genetics; Lymphocyte Count; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - immunology; Lymphopenia - immunology; Lymphopenia - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; T-Lymphocytes - virology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - deficiency; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.9.4859

4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB ligand (4-1BBL) on APCs. To investigate the role of 4-1BB costimulation for the development of primary immune responses, 4-1BBL-deficient (4-1BBL-/-) mice were infected with lymphocytic choriomeningitis virus (LCMV). 4-1BBL-/- mice were able to generate CTL and eliminate acute LCMV infection with normal kinetics, but CD8 T cell expansion was 2- to 3-fold lower than in wild-type (+/+) mice. In the same mice, virus-specific CD4 Th and B cell responses were minimally affected, indicating that 4-1BB costimulation preferentially affects CD8 T cell responses. This result contrasts with our earlier work with CD40L-deficient (CD40L-/-) mice, in which the CD8 T cell response was unaffected and the CD4 T cell response was markedly impaired. When both 4-1BBL- and B7-dependent signals were absent, CD8 T cell expansion was further reduced, resulting in lower CTL activity and impairing their ability to clear LCMV. Altogether, these results indicate that T cells have distinct costimulatory requirements: optimal CD8 responses require 4-1BBL-dependent interactions, whereas CD4 responses are minimally affected by 4-1BB costimulation, but require CD40-CD40L and B7-dependent interactions.