. 2015 Sep 5;6(27):23058–23134. doi: 10.18632/oncotarget.5492

Table 1. Bim Function in The Immune System.

Apoptotic Stimulus	Remarks	References
Negative selection of self-reactive thymocytes	• Thymocytes lacking Bim are refractory to apoptosis induced by TCR-CD3 stimulation. • Bim is required for apoptosis of CD4⁺CD8⁺ thymocytes induced by high-affinity antigens. • Bim is involved in clonal deletion of thymocytes recognizing tissue-restricted antigens (TRAs), but not superantigen-mediated apoptosis. • Autoreactive NODBim^−/− thymocytes receiving strong TCR signals that would normally delete them, escape apoptosis and are diverted into T_reg cells. • Bim is essential for deletion of CD4⁺CD8⁻CD24⁻ thymocytes in response to TCR ligation.	[40, 46, 401, 402, 404-406, 416]
Activated T cell death	• Bim is a key regulator of T cell apoptosis during the contraction phase of CD8⁺ T cell response. • Vβ8⁺ T cells from Bim-deficient mice are resistant to staphylococcus enterotoxin B-induced T cell death. • While the Bim levels did not change after exposure to staphylococcal enterotoxin B, the Bcl-2 levels decreased. • Shutdown of an acute T cell response to herpes simplex virus involved Bim. • Bim deficiency increases antigen-specific CD8⁺ T cell responses during viral infection.	[47, 395, 398, 399]
B7-H1 (PD-L1)-induced apoptosis of effector T cells	• B7-H1 (PD-L1) engagement with its receptor PD-1 promotes apoptosis of effector T cells through upregulation of Bim. • More memory CD8⁺ T cells were generated in B7-H1-deficient mice following immunization.	[409]
Elimination of poorly functional Th1 responder cells	• Rescued Bim^−/− CD4⁺ memory T cells showed deficient effector functions, poor sensitivity to antigen and an inability to respond to secondary challenge. • Bim mediates T cell death in the absence of appropriate TCR-driven activation and differentiation. • Bim shapes the CD4⁺ memory T cell repertoire by eliminating Th1 effector cells with suboptimal function, thereby ensuring the emergence of highly functional CD4⁺ memory cells.	[408]
Regulation of T memory cells	• The absence of Bim increased the effector CD8⁺ T cell population with more memory potential. • Survival of memory T cells depends on TRAF1-mediated Bim downregulation. • The absence of Bim-mediated death of lymphocytic choriomeningitis virus-specific CD4⁺ and CD8⁺ T cells in vivo leads to increased differentiation, even of CD127^lo T cells, into memory T cells.	[411, 422, 471]
Regulation of T regulatory cells	• In the absence of Bim, T regulatory cells accumulate rapidly, accounting for >25% of the CD4⁺ T cells in aged mice. • Rapid peripheral T regulatory cell turnover depends on Bim. • Induced regulatory T cells show decreased Bcl-2 expression and increased Bim expression and were more prone to apoptosis. • Rag^−/− hosts repopulated with Bim^−/− conventional CD4⁺ T cells resulted in a larger induction of regulatory T cells than mice given wild-type conventional CD4⁺ cells. • Bim deficient mice showed increased numbers of CD25^lowFoxp3⁺ cells in the thymus and peripheral lymph tissue. The CD25^lowFoxp3⁺ CD4⁺ cells were anergic and had weaker regulatory function than CD25^highFoxp3⁺ CD4⁺ T cells from the same mice.	[37-39, 394, 413]
B cell antigen receptor (BCR) stimulation-induced apoptosis	• B lymphocytes lacking Bim are refractory to apoptosis induced by BCR ligation. • The loss of Bim also inhibited deletion of autoreactive B cells in vivo in a B cell tolerance model. • Siglecs induce tolerance to cell surface antigens by Bim-dependent deletion of antigen-reactive B cells. • Cross-linked anti-μ antibodies that trigger apoptosis of human B lymphocytes, induce ERK-dependent downregulation of Bim_EL, with simultaneous upregulation of the Bim_L and Bim_S isoforms.	[36, 83, 429]
Elimination of autoreactive B cells	• Bim is involved in the elimination of autoreactive and anergic B cells.	[36, 426]
Superantigen-mediated B cell death	• The microbial virulence factor protein A of Staphylococcus aureus interact with evolutionarily conserved BCR-binding sites to induce a form of Bim-dependent activation-associated B cell death.	[427]
Apoptosis of low-affinity-expressing B cells.	• After immunization, Bim-deficient mice showed persistence of memory B cells lacking affinity-enhancing mutations in their immunoglobulin genes and antibody-forming cells secreting low-affinity antibodies.	[392]
Spontaneous and stress-induced apoptosis of granulocytes	• Bim deficiency renders granulocytes resistant to cytokine withdrawal and cytotoxic drugs such as etoposide and paclitaxel. • GM-CSF treatment temporarily blocks apoptosis by inducing Mcl-1 with rapid turnover and Bim, which limits GM-CSF-mediated prolonged survival of neutrophils.	[357, 433, 434]
Phagocytosis-induced apoptosis of macrophages	• Phagocytosis and intracellular killing of bacteria lead to apoptosis of macrophages that involve TLR-, p38- and JNK-dependent upregulation of Bim. • Phagocytosis-induced apoptosis was strongly reduced in Bim^−/− macrophages.	[430]
Spontaneous cell death of dendritic cells	• Bim-deficient dendritic cells showed decreased spontaneous cell death and induced more robust T cell activation.	[432]
Antigen-specific NK cell contraction	• Antigen-specific NK cell contraction after mouse cytomegalovirus infection depends on Bim.	[436]
Mast cell apoptosis	• Bim is induced together with Bcl-xL upon IgE receptor activation of mast cells.	[358]
Osteoclast apoptosis	• Liver X receptor activation leads to osteoclast apoptosis through Bim upregulation.	[645]
Cytokine deprivation	• Cytokine withdrawal leads to activation of FKHR-L1 in lymphocytes, which is responsible for the upregulation of Bim expression. •Early hematopoietic progenitor cells (Sca-1⁺, c-Kit⁺, Lin⁻) undergo rapid apoptosis in the absence of cytokines concomitant with Bim induction. • IL-3 signaling leads to phosphorylation of Bim_EL and its consequent degradation in hematopoietic stem cells. • IL-3 downregulates Bim through the Ras/MAPK and PI3K/Akt pathways. • M-CSF deprivation of osteoclasts leads to Bim-dependent apoptosis. • Bim deficiency prevented cytokine withdrawal-induced mast cell apoptosis. • PGE₂ increases mast cell death during cytokine deprivation by augmenting Bim expression.	[26, 122, 358, 360, 438, 646]
IL-21-induced apoptosis of CLL	• IL-21 induces apoptosis of chronic lymphoblastic leukemia (CLL) by activating the STAT-1 pathway and Bim induction. • IL-21 increased the cytotoxic effect of fludarabine and rituximab on CLL.	[190]