Knockdown of the Antiapoptotic Bcl-2 Family Member A1/Bfl-1 Protects Mice from Anaphylaxis

Ottina, Eleonora; Lyberg, Katarina; Sochalska, Maja; Villunger, Andreas; Nilsson, Gunnar

doi:10.4049/jimmunol.1400637

Cited by 20 publications

(14 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29,31 Therefore, we investigated mast cell numbers in the peritoneal cavity. Again, there were no differences in the numbers of mast cells between the A1-deficient and wild-type mice (Figure 5c).…”

Section: Figure 1 For Caption See Page 536mentioning

confidence: 99%

See 1 more Smart Citation

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

Self Cite

View full text Add to dashboard Cite

The pro-survival proteins of the BCL-2 family regulate the survival of all cells, and genetic deletion models for these proteins have revealed which specific BCL-2 family member(s) is/are critical for the survival of particular cell types. A1 is a pro-survival BCL-2-like protein that is expressed predominantly in haematopoietic cells, and here we describe the characterisation of a novel mouse strain that lacks all three functional isoforms of A1 (A1-a, A1-b and A1-d). Surprisingly, complete loss of A1 caused only minor defects, with significant, although relatively small, decreases in γδTCR T cells, antigen-experienced conventional as well as regulatory CD4 T cells and conventional dendritic cells (cDCs). When examining these cell types in tissue culture, only cDC survival was significantly impaired by the loss of A1. Therefore, A1 appears to be a surprisingly redundant pro-survival protein in the haematopoietic system and other tissues, suggesting that its targeting in cancer may be readily tolerated. Cell Death and Differentiation (2017) 24, 534-545; doi:10.1038/cdd.2016.156; published online 13 Janaury 2017The pro-survival proteins of the BCL-2 family prevent apoptosis 1 and studies using gene-targeted mice have revealed which cell types rely on which pro-survival protein for their survival. For example, Bcl-2 −/− mice exhibit thymic and splenic atrophy, a loss of fur pigment and die~30 days post birth from polycystic kidney disease, attributable to excess lymphocyte, melanocyte and renal epithelial cell apoptosis, respectively. 2-4 Bcl-X −/− mice die before E14.5 of embryonic development because of aberrant death of erythroid and neuronal cells. 5 The generation of chimaeric or tissue-specific Bcl-X −/− revealed a critical role for BCL-XL in the survival of developing lymphocytes 5 and platelets. 6,7 Mcl-1 −/− embryos die before implantation (E3.5), 8 but conditional Mcl-1 deletion models have demonstrated an essential role for MCL-1 in the survival of haematopoietic stem cells, lymphocytes, neurons and cardiomyocytes. 9-15 Bcl-W −/− mice have impaired spermatogenesis. 16,17 A1 remains the only pro-survival BCL-2 family member for which a knockout mouse strain has not been developed. A1 was first discovered as a GM-CSF-inducible gene with significant sequence similarity to BCL-2 and MCL-1, 18 and its human homologue BFL-1 was later identified in fetal liver. 19 Overexpression of A1 protected an IL-3-dependent cell line from growth factor deprivation-induced apoptosis, thus demonstrating its pro-survival function. 20 In mice, A1 expression is restricted to the haematopoietic compartment. 18 Human BFL-1 expression is more widespread, but also predominantly haematopoietic. 21 A1 can be upregulated by NF-κB signalling, and it has been proposed that A1/BFL-1 is important for the survival of several activated immune cell subsets through stimulation of antigen or cytokine receptors. [22][23][24][25] Studies of A1 in mice are complicated by the presence of multiple isoforms that are the result of gene duplication ev...

show abstract

Section: Figure 1 For Caption See Page 536mentioning

confidence: 99%

“…Other in vivo studies of A1 involved knockdown of all functional isoforms using transgenic expression of an shRNA. [30][31][32][33] A1 knockdown caused a reduction in B cells, mast cells and dendritic cells, but knockdown in these models was usually incomplete and hence not equivalent to a knockout.…”

mentioning

confidence: 99%

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is also noteworthy that the above mentioned and other RNAi-based A1-knockdown mouse models did not show any reductions in the numbers of mature, naive T cells or defects in T cell activation in culture. The lack of a T cell defect was originally ascribed to incomplete knockdown of A1 in activated T cells, 8,15 but our analysis here points towards functional redundancy between A1 and other pro-survival BCL-2 family members in the survival of quiescent as well as activated T cells.…”

mentioning

confidence: 85%

“…14 A1-knockdown studies using in vivo expression of shRNAs in the haematopoietic system suggested a role for A1 in mast cell maturation, 15 mature B cell survival 8 and early T cell development, 16 although not all of these phenotypes were found across the different mouse models analysed. To unambiguously determine the functions of A1, we developed an A1 knockout mouse strain in which all three functional paralogues of A1 (A1-a, A1-b and A1-d) had been deleted.…”

mentioning

confidence: 99%

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

et al. 2017

Self Cite

View full text Add to dashboard Cite

The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult. Here, we used the recently generated A1−/− mouse model to examine the role of A1 in T cell immunity. We confirmed rapid and strong induction of A1 protein in response to TCR/CD3 stimulation in CD4 + as well as CD8 + T cells. Surprisingly, on infection with the acute influenza HKx31 or the lymphocytic choriomeningitis virus docile strains mice lacking A1 did not show any impairment in the expansion, survival, or effector function of cytotoxic T cells. Furthermore, the ability of A1 −/− mice to generate antigen-specific memory T cells or to provide adequate CD4-dependent help to B cells was not impaired. These results suggest functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T celldependent immune responses. Cell Death and Differentiation (2017) 24, 523-533; doi:10.1038/cdd.2016.155; published online 13 January 2017On antigenic challenge, T lymphocytes need to rapidly switch from their IL-7/IL-7R-regulated naive, quiescent state 1,2 to a T cell antigen-receptor (TCR/CD3) stimulation-induced activation state. 3 In case of inappropriate stimulation of the TCR, for example, in the absence of co-receptor stimulation, this shift in the survival programme is not induced and leads to rapid T cell death. 4 Conversely, appropriately stimulated T cells expand rapidly, allowing accumulation of T cell clones expressing TCRs of high affinity for specific antigens. During this clonal expansion, BCL-2 family regulated apoptosis acts as a mechanism to remove low-affinity T cells, thereby ensuring the generation of a highly effective immune response.5 On infection clearance, most of the activated T cells are removed by apoptosis, 6 leaving only some T cells with antigen-specific high-affinity TCRs in reserve as longlived memory T cells. 7The BCL-2 family of proteins regulate apoptotic cell death, with the balance between pro-survival and pro-apoptotic family members determining whether a cell lives or dies. The expression of pro-survival BCL-2 family members is dynamically regulated during T cell activation.8 TCR/CD3 ligation leads to the downregulation of BCL-2 and induction of BCL-XL.3 Accordingly, Bcl-2 −/− mice display a loss of mature, unstimulated T cells, and the death of these cells can be prevented by TCR/CD3 stimulation.9 Interestingly, although BCL-XL is substantially upregulated on TCR/CD3 stimulation, its loss did not increase apoptosis or impair proliferation of T cells stimulated with mitogenic antibodies. 10 In contrast, MCL-1 has been shown to be a crucial pro-survival factor after T cell activation.11,12 A1 is a prosurvival BCL-2 family protein that has been proposed to be i...

show abstract

“…9 Interestingly, in this model, the number of mast cells in connective tissues was reduced and mice were protected from anaphylaxis. 10 However, this and another RNAi transgenic mouse line showed somehow conflicting data on B- and T cell development and activated B cells. 9 This might be explained by incomplete knockdown efficiency by or off-target effects of RNAi.…”

mentioning

confidence: 97%

The Bcl2a1 gene cluster finally knocked out: first clues to understanding the enigmatic role of the Bcl-2 protein A1

Berberich

Hildeman

2017

Cell Death Differ

View full text Add to dashboard Cite

Knockdown of the Antiapoptotic Bcl-2 Family Member A1/Bfl-1 Protects Mice from Anaphylaxis

Cited by 20 publications

References 27 publications

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

The Bcl2a1 gene cluster finally knocked out: first clues to understanding the enigmatic role of the Bcl-2 protein A1

Contact Info

Product

Resources

About