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* Department of Immunology and
Department of Medical Biophysics, University of Toronto, and
Advanced Medical Discovery Institute, Ontario Cancer Institute, University Health Network, Toronto, Canada; and
Interdisciplinary Research Center of Autoimmune Diseases and Department of Medicinal Sciences, A. Avogadro, University of Eastern Piedmont, Novara, Italy
CD28, ICOS, and 4-1BB each play distinct roles in the CD8 T cell response to influenza virus. CD28–/– mice are severely impaired in primary CD8 T cell expansion and fail to mount a secondary response to influenza. Influenza-specific CD8 T cells expand normally in ICOS–/– mice, with only a small and transient defect late in the primary response and an unimpaired secondary response. Conversely, 4-1BB/4-1BBL interaction is dispensable for the primary CD8 T cell response to influenza, but maintains CD8 T cell survival and controls the size of the secondary response. Previous results showed that a single dose of agonistic anti-4-1BB Ab at priming allowed partial restoration of primary CD8 T cell expansion and full recovery of the secondary CD8 T cell responses to influenza in CD28–/– mice. In this study we show that anti-4-1BB fails to correct the CD8 T cell defect in CD28–/–ICOS–/– mice, suggesting that ICOS partially compensates for CD28 in this model. In support of this hypothesis, we found that anti-4-1BB enhances ICOS expression on both T cell subsets and that anti-4-1BB and anti-ICOS can synergistically activate CD4 and CD8 T cells. Furthermore, ICOS and 4-1BB can cooperate to directly stimulate isolated CD28–/– CD8 T cells. These results reveal a novel interaction between the ICOS and 4-1BB costimulatory pathways as well as unexpected redundancy between CD28 and ICOS in primary CD8 T cell expansion. These findings have implications for costimulation of human T cell responses in diseases such as AIDS or rheumatoid arthritis, in which CD28– T cells accumulate.
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