Effect of presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells

Abstract

Many studies have positioned Notch signaling at various critical junctions during T-cell development. There is, however, debate regarding the role of Notch in the CD4 versus CD8 lineage commitment. Because there are 4 Notch receptors and RBP-J-independent Notch signaling has been reported, we decided to eliminate ␥-secretase activity once its activity is required for all forms of Notch signaling. T-cell-specific elimination of ␥-secretase was carried out by crossing presenilin-1 (PS1) floxed mice with CD4-Cre mice and PS2 KO mice, generating PS KO mice. Thymic CD4 ؉ CD8 ؉ double-positive (DP) cells from these mice were strikingly resistant to apoptosis by anti-CD3 treatment in vivo and expressed more Bcl-X L than control thymocytes, and deletion of only one allele of Bcl-X L gene restored wildtype levels of sensitivity to apoptosis. In addition, these PS KO animals displayed a significant decrease in the number of CD8 ؉ T cells in the periphery, and these IntroductionNotch signaling was first identified in strains of Drosophila flies that exhibit Notching at their wing edges, and subsequent analyses showed that Notch signals regulate cell fate, cell numbers via effects on proliferation and survival, and cell position, all of them dependent of dose, timing, and context of the Notch signal. 1 Nearly all aspects of invertebrate Notch signaling are recapitulated in mammals in which this pathway plays multiple roles in normal development and disease. 1,2 Engagement of Notch receptor by its ligands results in a series of proteolytic cleavage events that cause the release of the Notch intracellular domain (NIC). The final processing step of Notch is achieved by a ␥-secretase complex where presenilins (PSs) play a major role. 3 Indeed, the absence of PS function through genetic ablation or using ␥-secretase inhibitors induces a phenocopy of Notch loss of function. [4][5][6][7][8][9] Once NIC is in the nucleus, it interacts with RBP-J resulting in the transcription of several Notch targets such as hes, hrt, and deltex family members, or pre-T␣, to name a few. 10,11 It is important to note that Notch activities independent of RBP-J but linked to other proteins such as deltex have been described. 2,[12][13][14][15] Despite the crucial role of presenilins in the Notch pathway, PSs could also be directly involved in MAPK activation/ suppression, so it is also possible that any PS effect on the differentiation, activation, cell growth, and death of T cells could be independent of Notch signaling.Many studies have positioned Notch receptor-ligand interactions at various critical junctions in T-cell development, most notably in the T versus B lineage choice, a Notch role for which there is complete agreement. 16,17 In other set of studies, Notch1 signals have also been shown to promote the ␣␤ over the ␥␦ T lineage. 18 However, the effect of the Notch pathway in CD4 versus CD8 T-cell lineage commitment is controversial because overexpression of NIC1 or NIC2, but not NIC3, decreases the CD4/CD8 ratio in the thymus, 19-23 althoug...

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

“…A strong association between presenilins and the immune system has been reported from phenotypic characterization of several in vivo models of presenilin biology and identification of g-secretase substrates. The phenotype of PS1 +/-PS2 -/-partial deficient mice revealed a novel in vivo function for presenilins in the immune system [19], which has been substantiated in T cell and B cellspecific presenilin-deficient animals [25,26]. The PS1 +/-PS2 -/-animals are relatively normal up to about 6 months of age, after which the majority of the mice develop a systemic lupus erythematosus (SLE)-like autoimmune disease [19].…”

“…The PS1 +/-PS2 -/-animals are relatively normal up to about 6 months of age, after which the majority of the mice develop a systemic lupus erythematosus (SLE)-like autoimmune disease [19]. Ablation of presenilin in T cells results in inefficient generation of CD4+ T cells, a phenotype that correlates with evidence of impaired T cell receptor (TCR) signalling [25], while selective loss of presenilins in B cells compromises responsiveness to LPS and B cell antigen receptor-induced proliferation and signal transduction events [26]. Likewise, abnormal vasculogenesis and angiogenesis have been reported in PS1 and Aph-1a deficient mice [68,141].…”

“…The phenotype of PS1 +/-PS2 -/-partial deficient mice is normal up to approximately six months, when the majority of the mice develop skin lesions similar to seborrheic keratosis, the common benign wart seen frequently in elderly humans, and an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus [19]. Subsequent studies have also employed the Cre/LoxP system to more closely study the long-term role of PS1 in lymphoid T cells [25] and B cells [26]. Deficiency in both PS1 and PS2 functions antagonise T cell homeostasis and signalling [25], while B cells deficient in PS1 and PS2 present a deficit in both lipopolysaccharide (LPS) and B-cell antigen receptorinduced proliferation and signal transduction events [26].…”

“…Subsequent studies have also employed the Cre/LoxP system to more closely study the long-term role of PS1 in lymphoid T cells [25] and B cells [26]. Deficiency in both PS1 and PS2 functions antagonise T cell homeostasis and signalling [25], while B cells deficient in PS1 and PS2 present a deficit in both lipopolysaccharide (LPS) and B-cell antigen receptorinduced proliferation and signal transduction events [26]. From these studies it has been concluded that in addition to the central nervous system, the skin [20,27] and the immune system appear to be especially sensitive to a partial loss of presenilin functions [19,28].…”

Presenilin: RIP and beyond

“…Likewise, reduction in Notch activity in adult flies resulted in their death [33,34] arguing that loss of Notch activity may underly this phenotype. On the other hand, conditional deletion of PSEN1/PSEN2 in thymocytes increased their resistance to anti-CD3 induced apoptosis in vivo [159]. Thus, the effect of loss of PSENs on apoptosis most likely reflects their substrates or the cell type being analyzed.…”