Apoptosis of T Lymphocytes

Agonistic anti-CD137 mAb treatment inhibited the function of pathogenic CD4+ T cells in various autoimmune disease models (Seo etal., 2004; Shao etal., 2005; Sun et al., 2002b). Such treatment could also reduce CD4+ T cell number in certain models (Kim et al., 2005; Sun et al., 2002a, 2002b). In lpr mice, CD137 engagement with anti-CD137 resulted in the diminishment of CD4+ T cell number (Sun et al., 2002a). Through tracking antigen-specific T cell response with D011.10 TCR transgenic mice, which express transgenes encoding a TCR specific for chicken OVA peptide 329-339 bound to I-Adclass IIMHC molecule, and can be detected with mAbs specific for CD4 and the clonotypic TCR (KJ1-26), Sun et al. (2002b) found the administration of agonistic anti-CD137 initially enhanced antigen-specific CD4+ T cell expansion, but subsequently promoted their depletion by inducing their apoptosis.

In accordance with reduced CD4+ T cell number, in EAE and EAU models, anti-CD137 treatment initially promoted the function of autoreactive TH1 cells followed by diminishment of their functions (Shao et al., 2005; Sun et al., 2002b). Four to five days after immunization, draining lymph node (DLN) T cells from anti-CD137 treated mice showed increased proliferation and cytokine production such as IFN-y, GM-CSF and IL-2 compared with control IgG treated mice. However, 10 days after immunization, DLN T cells from anti-CD137 treated mice showed reduced proliferation and cytokine production compared with control mice. This is different from CTLA blockade with CTLA-Fc, which inhibited T cell function at both time points (Shao et al., 2005). When cultured ex vivo, DLN T cells from anti-CD137 treated mice manifested significantly increased apoptosis rate compared with that of control mice (Shao et al., 2005). These studies suggest CD137 signaling plays diametric role in CD4+ T cell-mediated immune responses, it initially promoted CD4+ T cell activation and then increased their activation induced cell death (AICD) leading to diminished helper T cell function. This dual-phase outcome of CD137 signaling on CD4+ T cells was also observed in cGVHD model (Kim et al., 2005). Agonistic anti-CD137 treatment promoted the activation and proliferation of donor CD4+ T cells at the initial phase of cGVHD and followed by increased donor CD4+T cell apoptosis, leading to the reduction of donor CD4+ T cell number in the spleen.

In addition to CD4+ T cells, CD137 engagement induces drastic diminish-ment of DNTC population with increased apoptosis, which leads to the attenuation of lymphadenopathy in MRL/lpr mice (Sun et al., 2002a).

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