Induction of tolerance using Fas ligand: a double-edged immunomodulator

Abstract

Fas/FasL system and immune homeostasisThe immune system functions in complex and dynamic microenvironments, where decisions pertaining to the survival and/or physical elimination of antigen-specific T-cell clones are critical to the establishment and maintenance of functional immunity. Activationinduced cell death (AICD) is the primary homeostatic mechanism used by the immune system to control T-cell responses, promote tolerance to self-antigens, and prevent autoimmunity. [1][2][3] Following activation, T cells express Fas and Fas ligand (FasL) and upon repeated antigenic stimulation become sensitive to Fas/FasLmediated autocrine and paracrine apoptosis (Figure 1). [4][5][6] These 2 modes of apoptotic cell death serve to control the pool size of antigen-activated T-cell clones and regulate immune responses. 7 All lymphocytes, including CD4 ϩ and CD8 ϩ T, B, and natural killer (NK) cells as well as dendritic cells, monocytes, macrophages, and neutrophils are subject to Fas/FasL-regulated immune homeostasis. [8][9][10][11] Dysregulation of Fas/FasL-mediated AICD is associated with a series of pathophysiologic conditions, including degenerative and autoimmune disorders. 12 Mouse strains that lack Fas (lpr) or express a defective FasL molecule (gld) suffer from severe lymphoproliferative disorders and autoimmunity, 12,13 arising from the absence of antigen-induced clonal T-cell deletion in the periphery. 14,15 Similarly, the autoimmune lymphoproliferative syndrome in humans, an inherited disorder of lymphocyte homeostasis, is associated with the lack of AICD due to defects in Fas, FasL, and effector caspases. 16 Fas is a 45-kDa, type I cell surface protein with an extracellular domain that binds to FasL and a cytoplasmic domain that transduces the death signal. 17 Apoptosis is executed by the engagement and coaggregation of FasL with the Fas receptor on the cell surface followed by a series of intracellular molecular interactions that coordinate the hierarchical activation of caspases and cell death (Figure 2). Oligomerization of Fas following FasL engagement leads to the recruitment of Fas-associated proteins having death domains and the initiator procaspase-8 via its death effector domain into a death-inducing signaling complex (DISC). [18][19][20] Procaspase-8 undergoes autoproteolysis in the DISC complex to generate an active caspase-8, which in turn initiates extrinsic apoptosis by converting inactive effector procaspases-3, -6, and -7 into active enzymes via transproteolysis and intrinsic apoptosis via cleavage of Bid, release of cytochrome c, and activation of caspase-9. 18,21 Executioner caspases cleave various vital cellular substrates, which leads to cell death.FasL is a 40-kDa, type II cell surface protein that is inducibly expressed in lymphocytes, particularly T cells, 22 and constitutively expressed in cells present in immune privileged organs, such as Sertoli cells of the testis and epithelial cells in the eye. 23,24 Inasmuch as FasL-mediated apoptosis is critical to peripheral T-cell homeostasis...

The effects of FasL on inflammation and tumor survival are dependent on its expression levels

“…Earlier studies indicated that the membrane bound FasL may be released from cell surface after protease-mediated cleavage and the soluble form may act as a chemotactic factor that induces the migration of neutrophils. 3,22 In contrast, we have found that soluble form of FasL did not trigger apparent inflammation or tumor rejection. 23 A recent study provided evidence that FasL-triggered inflammation correlated with its cytotoxic activity and was in fact a secondary effect of the locally induced apoptosis.…”

“…[1][2][3] FasL is expressed in the eye and testis where its pro-apoptotic activity, along with a variety of other immunosuppressive factors, is considered to contribute to the immune privilege status of these tissues. [3][4][5][6] FasL is also expressed by many human tumors and is associated with poor prognosis in breast, 7,8 ovarian 9 and liver 10 cancers, leading to the hypothesis that tumors use FasL to counterattack the tumorinfiltrating cytotoxic T cells and to escape the immune clearance. 11,12 In contrast to these observations, tumor cells engineered to express exogenous FasL triggered a potent neutrophil-mediated local inflammatory response and were rapidly rejected.…”

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

“…[10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the high specificity since only T cells responding to the antigen expressed on the APC are deleted by CD95/CD95L interaction while the remaining T cells are still responsive to unrelated antigens.…”

The fate of transplanted xenogeneic bone marrow‐derived stem cells in rat intervertebral discs

“…35,36 Fas-L mediated T-lymphocyte apoptosis in immune privileged sites might protect the tissue/site from immune damage, thereby inducing immune tolerance. 37 In other studies Fas-L protein has been implemented in the reduction of allogenic rejection independent of apoptotic induction. 38,39 In our study, the Fas-L protein was upregulated by both the host and injected cells following transplantation, especially at day 10 when CD34 À cells were used.…”