Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity

Abstract

IntroductionDendritic cells (DCs) represent the most efficient antigenpresenting cells in capturing, processing, and presenting antigens for lymphocyte activation. [1][2][3][4][5] Several studies have shown that DCs undergo rapid turnover in vivo. [6][7][8][9] DCs may also undergo accelerated clearance from the lymphoid organs after interacting with antigen-specific T cells. 6 It is possible that the life span of DCs can influence their duration for stimulating lymphocytes, thereby affecting the outcome of lymphocyte activation and immune responses. In support of this possibility, ablation of DCs with diphtheria toxin in transgenic mice has been shown to impair the priming of antigen-specific cytotoxic T cells, 10 while inhibition of apoptosis in DCs enhances the antigen-specific immune responses. 8 Apoptosis plays essential roles in multiple cellular processes, including development, tissue homeostasis, immune tolerance, and immune surveillance. [11][12][13] The critical role for apoptosis in maintaining peripheral tolerance is demonstrated by systemic autoimmune diseases that result from mutations in the proapoptotic Fas receptor or Fas ligand genes, in both humans and mice. [12][13][14] DCs may contribute to the maintenance of immune tolerance. 5,15,16 We have observed that targeted inhibition of apoptosis in DCs with p35, a caspase inhibitor that preferentially targets caspase-8 in the Fassignaling pathway, 17 can induce spontaneous T-cell activation and the development of systemic autoimmunity in transgenic mice. 18 However, whether other apoptosis pathways in DCs help to regulate self-tolerance remains to be tested.The Bcl-2 family proteins are critical regulators of mitochondrial apoptosis pathway. 19,20 They share one or more Bcl-2 homology (BH) domains and can be divided into 3 subfamilies, 19,20 including the antiapoptotic subfamily proteins, such as Bcl-2, Bcl-xL, and Mcl-1; the proapoptotic Bax-and Bak-like proteins; and the proapoptotic BH3-only subfamily, such as Bim and Bid. In particular, BH3-only proteins emerge as the upstream sensors for different apoptosis signaling in specific cell types. 21 BH3-only proteins either inhibit the antiapoptotic molecules as "derepressors" or directly activate proapoptotic Bax or Bak to induce apoptosis. 21,22 Bcl-2 family proteins may also play important roles in the regulation of apoptosis in DCs. 8,9 It has been shown that overexpression of Bcl-2 in DCs can prolong DC survival and enhance the immunogenicity of DCs in transgenic mice. 8 This suggests that the mitochondrion-dependent apoptosis regulated by Bcl-2 family proteins may play an important role in regulating DC survival and functions.Bim is a proapoptotic BH3-only protein in the Bcl-2 family that has been shown to play a critical role in regulating homeostasis of lymphocytes. 21,23 Although Bim can be rapidly induced in DCs by different stimuli, 9 whether apoptosis and homeostasis of DCs can be regulated by Bim has not been determined. Deficiency in Bim causes significant expansion of lymphocytes and ...

Apoptosis and the homeostatic control of immune responses

“…Mice containing such DCs have increased numbers of activated T cells and anti-nuclear-antigen antibody production [14]. In contrast, mice whose DCs overexpress a hBcl-2 transgene or lack Bim have increased steady-state levels of DCs in relatively young mice, which can elicit increased T cell responses and autoantibody production [11,15]. Thus, both death receptors and Bcl-2 family members contribute to the demise of DCs following their activation, suggesting that DCs with extended life times can enhance T and B cell responses.…”

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

“…18 Further, other data suggest that dendritic cell (DC) expression of Bim can control the magnitude of T-cell responses. 19 Thus, the cell-specific roles of Bim and the potential contributions of other proapoptotic Bcl-2 family members remain unclear.…”

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

“…In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].Immature DC have the ability to acquire protein complexes or soluble antigen using many different pathways such as macropinocytosis, endocytosis and even through ingestion of entire cells. Despite the importance of DC apoptosis in the immune response, studies have not investigated the effects of DC death on viable DC.…”

“…In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].…”