Loss of Bim Increases T Cell Production and Function in Interleukin 7 Receptor–deficient Mice

Abstract

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Rα chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Rα–deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Rα double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Rα−/− mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7–deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.

Apoptosis in the development of the immune system

“…45 Indeed, when BIM-deficient animals were bred to IL-7R-deficient mice, there was a partial rescue of thymocytes development and a near restoration of mature T-cells in the periphery. 46 These data imply that while BIM is not the sole mediator of apoptosis in developing T-lymphocytes, it plays a substantial role in mediating death downstream of growth factor withdrawal. It has been demonstrated that loss of PUMA in cultured myeloid cells rendered these cells resistant to growth factor withdrawal.…”

Life in the balance: how BH3-only proteins induce apoptosis

“…Bim is crucial not only for eliminating lymphocytes that recognize self-antigens, during the development of both T cells [45] and B cells [46], but also for terminating T cell immune responses [47,48]. Furthermore, the lymphopenia provoked by loss of the Interleukin-7 receptor is alleviated by loss of Bim [49]. Bim also ensures the death of granulocytes [50], osteoclasts [34], mast cells [51] and neurons [52,53] upon cytokine deprivation.…”

Foxo‐mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3‐only protein

“…As Bim is critical for cytokine deprivation-induced apoptosis in diverse hematopoietic cell subsets [5,16], it was concluded that growth factor withdrawal kills cells through transcriptional upregulation of Bim by Foxo3a [11][12][13][14].…”