Dendritic Cell Apoptosis in the Maintenance of Immune Tolerance

Abstract

Apoptosis in the immune system is critical for maintaining self-tolerance and preventing autoimmunity. Nevertheless, inhibiting apoptosis in lymphocytes is not alone sufficient to break self-tolerance, suggesting the involvement of other cell types. We investigated whether apoptosis in dendritic cells (DCs) helps regulate self-tolerance by generating transgenic mice expressing the baculoviral caspase inhibitor, p35, in DCs (DC-p35). DC-p35 mice displayed defective DC apoptosis, resulting in their accumulation and, in turn, chronic lymphocyte activation and systemic autoimmune manifestations. The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance.

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

“…Systemic autoimmune diseases can be modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. Our study shows that in addition to the dogma of DC apoptosis as a mechanism to eliminate activated DC to prevent hyperactivation of the immune response, DC apoptosis also plays an active role in induction and maintenance of tolerance through induction of Treg, whereby defects in DC apoptosis may trigger autoimmunity.…”

“…DC apoptosis in itself is an important event for maintenance of tolerance. Defects in DC apoptosis have been linked to the development of autoimmunity with systemic autoimmune diseases modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. However, it is unclear how defects in DC apoptosis can trigger autoimmune responses.…”

“…We need to be cautious in interpreting our findings because our data indicates that several fold higher amounts of apoptotic DC are required than live DC for tolerance induction. However, in certain pathologies, such as sepsis, there could be local environments within lymphoid organs where apoptotic DC could potentially outnumber live DC.Systemic autoimmune diseases can be modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. Our study shows that in addition to the dogma of DC apoptosis as a mechanism to eliminate activated DC to prevent hyperactivation of the immune response, DC apoptosis also plays an active role in induction and maintenance of tolerance through induction of Treg, whereby defects in DC apoptosis may trigger autoimmunity.…”

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

“…Apoptosis in the immune system is critical for maintaining selftolerance and preventing autoimmunity. The death of CD4 þ T cells, CD8 þ T cells and even DC, 34 all contribute to selftolerance. Our findings and other groups' work revealed that the suppression mediated by Treg appears, at least in part, to be by the induction of apoptosis in these effector cells.…”

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

“…2 In addition to T cells, live and death of antigenpresenting cells, which initiate T cell responses has to be tightly controlled to avoid the establishment of autoimmunity. 3 Activation-induced cell death (AICD) represents an apoptosis mechanism mediated via the interaction of CD95 with its ligand CD95L, to mediate T cell death and initiate the termination of an immune response to maintain tolerance to self antigens and to prevent autoimmunity. 4 Owing to the constitutive expression of CD95L in immune privileged organs such as testis or eye, 5,6 CD95L was considered as an immunoprotective agent able to counterattack activated T cells in vivo.…”