4-1BB Stimulation Research Articles

4-1BB costimulation enhances HSV-1-specific CD8 + T cell responses by the induction of CD11c +CD8 + T cells

Since 4-1BB plays a predominant role in CD8 + T cell responses, we investigated the effects of 4-1BB triggering on the primary and memory CD8 + T responses to HSV-1 infection. 4-1BB was detected on 10–15% of CD4 + and CD8 + T cells following the infection. 4-1BB-positive T cells were in the proliferative mode and showed the enhanced expression of anti-apoptotic proteins. Agonistic anti-4-1BB treatment exerted preferential expansion of CD8 + T cells and gB/H-2K b-positive CD8 + T cells, and enhanced cytotoxicity against HSV-1 that was mainly mediated by CD11c +CD8 + T cells. CD11c +CD8 + T cells were re-expanded following re-challenge with HSV-1 at post-infection day 50, indicating that CD11c +CD8 + phenotype was maintained in memory CD8 + T cell pool. Our studies demonstrated that 4-1BB stimulation enhanced both primary and memory anti-HSV-1 CD8 + T cell responses, which was mediated by a massive expansion of antigen-specific CD11c +CD8 + T cells.

Modulation of Cord Blood CD8+ T Cell Effector Differentiation by 4-1BB and CD30: Cross-Talk with TGF-β1.

Transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, potently suppressed cytotoxic T lymphocyte (CTL) differentiation of human cord blood naïve CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. In contrast, 4-1BB (CD137), a costimulatory molecule in the TNF receptor family, promoted effector and memory CTL differentiation. We present evidence that the suppressive TGF-β1 effects can be effectively reversed by anti-4-1BB costimulnation during in vitro CTL differentiation driven by IL-15 from exclusively naïve cord blood CD8+ T cells. 4-1BB may counteract TGF-β1 effects at the level of TGF-β1 signaling by inhibiting Smad2 phosphorylation induced by TGF-β1. In contrast to 4-1BB, recent studies show that CD30, another member of the TNF receptor family, may play an important role in down-modulating effector or memory CTL responses. Thus, we hypothesized that CD30 may interact with 4-1BB in responding to the TGF-β1 suppression. TGF-β1 inhibits 4-1BB expression on CTLs. Conversely, TGF-β1 greatly up-regulates CD30 expression. IL-4 augments the TGF-β1-mediated up-regulation of CD30 expression resulting in further increase of CD30 expression. In contrast, IL-12 abrogates TGF-β1-induced CD30 expression. Such IL-4 and IL-12 effects on CD30 expression appear to be exactly opposite for 4-1BB expression: down- and up-regulating 4-1BB expression, respectively. Co-engagement of CD30 abrogates 4-1BB expression as well as its activity for reversing TGF-β1-mediated suppression of CTL proliferation particularly in the presence of IL-4. Expression of NKG2D, an important stimulatory receptor for NK and CTL cytotoxic activity is inhibited by TGF-β1. 4-1BB stimulation restores the NKG2D expression inhibited by TGF-β1. Again, co-engagement of CD30 significantly inhibits the 4-1BB activity for restoration of NKG2D expression. Taken together, our data suggest that 4-1BB promotes effector CTL differentiation and CD30 acts as a negative feed-back molecule, promoting TGF-β1-mediated CTL suppression and counteracting 4-1BB activity. In conclusion, we have delineated a novel link between CD30 expression and TGF-β1 which is pivotal to the down-regulation of 4-1BB-induced CTL effector differentiation.

4-1BB and OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus boost vaccine.

4-1BB (CD137) is a tumour necrosis factor receptor (TNFR) family member, expressed primarily on CD8 T cells after activation. Signalling through 4-1BB has been reported to enhance CD8 T-cell expansion and to protect activated CD8 T cells from death, resulting in an enlarged memory population. Although stimulating 4-1BB has been shown to significantly improve the immune response to weak immunogens such as tumours, little is known about its effect on the CD8 T-cell response to a powerful viral vector such as vaccinia. To test 4-1BB's ability to improve the murine CD8 T cell response to a DNA prime, poxvirus boost vaccine, similar to those used for human immunodeficiency virus and simian immunodeficiency virus vaccines, we administered 4-1BB agonist antibody at the time of the poxvirus boost. 4-1BB stimulation increased the number of functional memory CD8 T cells by two- to fourfold. However, we saw a similar enhancement at the peak of the response and in the memory phase, thus we found no evidence in the context of virus infection that 4-1BB stimulation could increase the percentage of CD8 T cells that survive the acute activation phase to become memory cells. OX40 (CD134) is an analogous TNFR family member expressed primarily on activated CD4 T cells. OX40 stimulation increased the number of antigen-specific CD4 T cells approximately threefold. Stimulating both 4-1BB and OX40 enhanced the CD8 T-cell response more than 4-1BB alone. Thus stimulating these receptors can improve the response to a powerful virus vector, and may be useful in vaccine development.

4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1.

4-1BB, a T cell costimulatory receptor, prolongs CD8(+) T cell survival. In these studies, 4-1BB stimulation was shown to increase expression of the antiapoptotic genes bcl-x(L) and bfl-1 via 4-1BB-mediated NF-kappaB activation. This signaling pathway was specifically inhibited by PDTC and was different from the pathways that enhanced CD8(+) T cell proliferation. The results suggest a role for the antiapoptotic activities of Bcl-x(L) and Bfl-1 proteins in 4-1BB-mediated CD8(+) T cell survival in vivo.