4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses

Abstract

Our previous study has demonstrated that there is a significant delay of Balb/c cardiac allograft rejection in the C57BL/6 4-1BB-deficient knockout recipient. In this study, we examined the effect of combined blockade of the 4-1BB and CD28 costimulatory pathways on cardiac allograft rejection in the C57BL/6 → Balb/c model. A long-term cardiac allograft survival was induced in CD28/4-1BB-deficient mice (＞ 100 days survival in 3 of 4 mice), which was comparable with CD28-deficient mice (＞ 100 days survival in 2 of 5 mice; P ＜ 0.2026). There was no long-term cardiac allograft survival in either wild-type (WT) or 4-1BB-deficient mice, even though 4-1BB-deficient recipients showed a significant delay of cardiac allograft rejection than WT mice. An in vitro mixed leukocyte reaction (MLR) assay showed that 4-1BB-deficient and WT mouse T cells had a similar responsiveness to allostimulation, whereas CD28-and CD28/4-1BB-deficient mouse T cells had a defective responsiveness to allostimulation. Furthermore, 4-1BB-deficient mice showed a similar CTL but an elevated Ab response against alloantigens as compared to WT mice, and the alloimmune responses of 4-1BB-deficient mice were abrogated in the CD28-deficient background. Overall, these results indicate that the CD28 costimulatory pathway plays a major role in the alloimmune response and that 4-1BB signals are dependent upon CD28 signals.

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

“…14 CD137 has been shown to be essential for B-cell function, including activation, affinity maturation, proliferation, and class switch recombination (CSR) through its interaction with CD137L in germinal centers. [14][15][16] We thus hypothesized that these functions may be impaired in patient B cells. Indeed, CD137 expression was abrogated in B cells from all patients (Figure 1F), and B-cell activation was impaired (Figure 2G).…”

In Vitro Stimulation and Expansion of Human Tumour‐Reactive CD8+ Cytotoxic T Lymphocytes by Anti‐CD3/CD28/CD137 Magnetic Beads

“…Hence, we used magnetic beads (Dynabeads) coated with mAbs for CD3, CD28 and CD137 as novel artificial APCs to provide activation ‘signal 1’ via the TCR and to combine it with a strong costimulatory ‘signal 2’. Because it is not yet clear from the literature, whether CD137 acts as an independent costimulatory signal [31, 32] or is depending on CD28 signalling [33, 34], we applied CD3/CD28/CD137 beads and compared them with conventional CD3/CD28 beads. Some studies have already indicated that binding of agonistic antibodies to CD137 mediates an antigen‐independent growth signal for T lymphocytes with memory phenotype [35].…”

Integration of the Innate and Adaptive Immunity by CD137-CD137L Bidirectional Signals: Implications in Allograft Rejection

“…CD137 is a member of the TNF receptor family and its expression is inducible in T cells (14,15). Induction of CD137 can be triggered by TCR signaling and CD28 signaling further increases TCR-mediated upregulation of CD137 expression, suggesting that CD137 signaling is dependent upon CD28 signaling (16). Nonetheless, CD137 is thought to have distinct roles in T-cell-mediated immune responses.…”