The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells

Abstract

What makes a protein immunogenic, particularly for strong T cell-mediated immunity? To a first approximation, this determination seems to be made by dendritic cells (DCs). Immature DCs, as in skin (1-4), lung ( 5), blood (6, 7), and spleen (7, 8), take up proteins, immune complexes, microbes, and dying cells. However, in order to use these antigens to stimulate a T cell response, the DCs must undergo a characteristic process of terminal differentiation called "maturation." The known stimuli for DC maturation are numerous and include inflammatory cytokines, CD40 ligand (CD40L), viral and microbial constituents such as doublestranded RNA and LPS, and certain CpG oligonucleotides. DC Maturation as a Control Point in the Initiation of ImmunityMaturation changes DCs in many ways that help explain their potent immunogenicity. Examples include de novo expression of T cell costimulatory molecules like CD86 (9, 10); the capacity to produce 12) and resist immunosuppression by IL-10 (13); the development of a new repertoire of chemokine receptors, especially CCR7 (14-17), that guide entry into lymphatics and migration to the T cell areas (18); the production of DC survival and stimulatory molecules like CD40 and TNF-related activation-induced cytokine receptor (TRANCE-R) (19, 20); and a redistribution of MHC class II molecules from lysosomes to the cell surface (21,22). Recently, it has been found (Inaba, K

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

“…Apoptotic cells are endowed with immunomodulatory properties. 16,17 Macrophages involved in apoptotic cell capture have been described to release TGF-b both in vitro 19 and in vivo. 26 A previous in vitro study reported that TGF-b was specifically released by macrophages ingesting apoptotic cells, but not during any other type of phagocytosis.…”

“…DC subsets have also been implicated in apoptotic cell uptake 17,[20][21][22][23] and subsequent T-cell cross-tolerization. [20][21][22] In our model, we found fluorescent apoptotic bodies in splenic DC, suggesting that apoptotic cell-derived Ag can also be processed by some DC subsets.…”

“…Several peripheral tolerance mechanisms explaining the absence of immune responses against apoptotic cell-derived Ags have been proposed. [16][17][18] First, professional phagocytes, such as macrophages 19 or certain dendritic cells (DC) subsets, [20][21][22][23] quickly capture apoptotic bodies, thereby preventing the release of harmful products from dying cells. 24 In addition, apoptotic cell death is frequently associated with an immunomodulatory milieu that may neutralize immune cells present in the environment of dying cells.…”

Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

“…Mature DCs express high levels of major histocompatibility complex (MHC) class I, II and co-stimulatory molecules such as CD80 and CD86, and secrete T-helper type-1 (Th1) cytokines such as interleukin (IL)-12 and interferon (IFN)-g. DCs acquire endogenous maturation stimuli from dying cells as a danger signal when they capture cellular antigens. Lack of danger signals delays maturation of DCs and causes active suppression of DCs stimulatory capacity, leading to the induction of T-cell tolerance (Steinman et al, 2000). Shi et al (2003) have previously identified uric acid as a novel endogenous warning molecule capable of alerting the immune system within cell lysates.…”

Immunopotentiation of the antibody response against influenza HA with apoptotic bodies generated by rabies virus G-ERA protein-driven apoptosis

“…Furthermore, the role of apoptosis in the induction or prevention of an immune response is still unclear. Indeed, some groups have demonstrated that the uptake of apoptotic cells by DC results in T cell tolerance [4][5][6]. Conversely, other groups have shown that DC that have phagocytosed apoptotic bodies from virus-infected cells can present viral antigens to cytotoxic T cells and induce a cytotoxic response [7,8].…”