Abstract
Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR–calcineurin–nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.
Highlights
The physiological regulation of apoptosis in lymphocytes has been extensively investigated,[8] and may assume a new relevance in the context of therapeutic approaches selectively targeting B-cell lymphoma 2 (Bcl-2) proteins
We found a unique selectivity profile of ABT-737 on T lymphocytes over the course of the immune response as a result of a transient, calcineurin, nuclear factor of activated T cells (NFAT)- and A1-dependent resistance to ABT-737 after antigen recognition
To investigate the impact of allogeneic T-cell activation on the sensitivity to the Bcl-2 inhibitor ABT-737, we used the transgenic mouse strain BM3.3, which expresses on all CD8 T cells a transgenic T-cell receptor (TCR) specific for the major histocompatibility complex (MHC) class I molecule H-2Kb and can be detected by the clonotypic antibody Ti98
Summary
Activated T cells are resistant to ABT-737. To investigate the impact of allogeneic T-cell activation on the sensitivity to the Bcl-2 inhibitor ABT-737, we used the transgenic mouse strain BM3.3, which expresses on all CD8 T cells a transgenic TCR specific for the major histocompatibility complex (MHC) class I molecule H-2Kb and can be detected by the clonotypic antibody Ti98. We transplanted BM3.3 bone marrow into non-lethally irradiated CBA mice to create synchimeric mice that express the BM3.3 TCR only on a fraction of the CD8 T-cell pool. This well-defined homogeneous population of alloreactive CD8 T cells could be followed during the course of an HvG response in the context of an otherwise physiological immune system (Figures 1a and b). The percentage of Ti98 þ cells among CD8 T cells increased in both groups, but this effect was markedly enhanced in the ABT-737 group compared with control (Figure 1e). This observation is explained by a selection of activated Ti98 þ cells among CD8 T cells under the effect of ABT-737, which
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