Immune Responses in 4-1BB (CD137)-Deficient Mice

Abstract

The 4-1BB (a TNFR superfamily member) is an inducible costimulatory molecule that can exert regulatory effects on T cells independently of CD28 stimulation. The in vitro expression of 4-1BB (CD137) is induced following activation of T cells with various stimuli, including anti-TCR mAbs, lectins, and a combination of PMA and ionomycin. To delineate further the physiological role of 4-1BB in immunity, mice deficient in this receptor were generated. These mutant mice developed normally, and were viable and fertile. Humoral responses to vesicular stomatitis virus were comparable with those seen in wild-type mice, whereas the IgG2a and IgG3 isotype responses to keyhole limpet hemocyanin were somewhat reduced in the mutant mice. The 4-1BB-deficient mice demonstrated enhanced T cell proliferation in response to mitogens or anti-CD3 even in the environment of reduced ability to secrete growth-supporting cytokines (IL-2 and IL-4). Although T cells from 4-1BB-deficient mice showed enhanced proliferation, the T cell immune responses of these animals, such as cytokine production and CTL activity, were diminished. In addition, 4-1BB deletion appears to play a role in the regulation of myeloid progenitor cell growth, leading to an increase in these precursor cells in peripheral blood, bone marrow, and spleen.

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

“…Although the increased NFATc1 expression by r4-1BBL does not fit with this possibility (Fig. 5C), a similar discrepancy has been reported for the role of 4-1BB in T cell proliferation: 4-1BB -/-T cells show an increased proliferative response compared with 4-1BB +/+ T cells, despite the costimulatory effect of 4-1BBL on the proliferation of 4-1BB +/+ T cells [29,30]. The exact signaling pathways through 4-1BB and 4-1BBL warrant further clarification.…”

“…The quite mild phenotype of 4-1BB -/-mice despite the reduced osteoclastogenic ability ex vivo may be attributed to increased myeloid cells in these mice [29] or may implicate redundancy of the 4-1BBL/4-1BB axis in normal bone homeostasis. However, 4-1BBL and 4-1BB may have an additional role in inflammation.…”

“…The 4-1BB +/+ and 4-1BB -/-mice [29] with C57BL/6 background were purchased from the Immunomodulation Research Center (Ulsan University, Ulsan, Korea). The animals were housed in SPF conditions and bred at the Laboratory Animal Facility in the School of Dentistry, Seoul National University.…”

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.…”

“…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.…”