Temporal Segregation of 4-1BB Versus CD28-Mediated Costimulation: 4-1BB Ligand Influences T Cell Numbers Late in the Primary Response and Regulates the Size of the T Cell Memory Response Following Influenza Infection

Abstract

In this report, we demonstrate that CD28−/− mice are severely impaired in the initial expansion of Db/NP366-374-specific CD8 T cells in response to influenza virus infection, whereas 4-1BB ligand (4-1BBL)−/− mice show no defect in primary T cell expansion to influenza virus. In contrast, 4-1BBL−/− mice show a decrease in Db/NP366-374-specific T cells late in the primary response. Upon secondary challenge with influenza virus, 4-1BBL−/− mice show a decrease in the number of Db/NP366-374-specific T cells compared to wild-type mice such that the level of the CD8 T cell expansion during the in vivo secondary response is reduced to the level of a primary response, with concomitant reduction of CTL effector function. In contrast, Ab responses, as well as secondary CD4 T cell responses, to influenza are unaffected by 4-1BBL deficiency. Thus, CD28 is critical for initial T cell expansion, whereas 4-1BB/4-1BBL signaling affects T cell numbers much later in the response and is essential for the survival and/or responsiveness of the memory CD8 T cell pool.

Expression and function of 4‐1BB during CD4 versus CD8 T cell responses in vivo

“…3), previous studies showed that CD8 + T cell expansion and contraction during the first 2 weeks of the immune response to influenza virus is indistinguishable between WT and 4-1BBL -/-mice [26]. Therefore, it was important to compare the CD8 + T cell response in a similar system to that used above for OT-II cells.…”

“…Administration of agonistic antibodies to 4-1BB during superantigen responses led to amelioration of T cell deletion, with preferential effects on CD8 + T cells [21]. Gene-targeted mice revealed a role for 4-1BBL in secondary CD8 T cell responses to viruses with no detectable effect on CD4 + T cell responses [26][27][28][29]. This suggested that under physiological conditions in vivo, the 4-1BB costimulatory pathway was more important for CD8 + than for CD4 + T cells [30].…”

4-1BB (CD137) Ligand Enhanced Anti-Tumor Immune Response against Mouse Forestomach Carcinoma In Vivo

“…Bertram et al demonstrated that the T-cell immune responses of 4-1BB -/-mice, as measured by cytokine production and CD8 + T-cell cytotoxic T lymphocyte activity, were diminished (20). It has been confirmed that in conjunction with "signal one", the interaction of 4-1BB/ 4-1BBL provides co-stimulatory signals to T cells through the activation of NF-κB, c-Jun and p38 downstream pathway (21).…”

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

“…The existence of 4-1BB À/À and 4-1BBL À/À knockout mice 38,39 has allowed a number of investigations into the necessity of 4-1BB:4-1BBL in immune responses. Kwon et al 39 showed that T cells from 4-1BB À/À mice had enhanced proliferation in response to mitogens, or a-CD3.…”

“…However, the T-cell immune responses of 4-1BB À/À mice, as measured by cytokine production and CD8 þ Tcell cytotoxic T lymphocyte (CTL) activity, were diminished. In 4-1BBL À/À mice, Bertram et al 38 showed that in the initial expansion of D b /NP366-374-specific CD8 þ T cells in response to influenza virus infection, 4-1BBL À/À mice showed a decrease in virus-specific T cells late in the primary response. In mice, it has been shown that in conjunction with ''signal one'', the interaction of 4-1BBL with 4-1BB provides costimulatory signals to both CD4 þ and CD8 þ T cells through the activation of NF-kB, c-Jun and p38 downstream pathways (Fig 3).…”