Immune privilege and FasL: two ways to inactivate effector cytotoxic T lymphocytes by FasL‐expressing cells

Li, Jie-Hui; Rosen, Dalia; Sondel, Paul M.; Berke, Gideon

doi:10.1046/j.1365-2567.2002.01380.x

Cited by 36 publications

(42 citation statements)

References 36 publications

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“…On the one hand, an increased number of apoptotic T cells has been found in CD95L + tumors in situ [20,22], and in vitro studies show that activated T cells are CD95-sensitive [35,38]. On the other hand, CD95L expression leads to rejection or slower growth of tumors in mice.…”

Section: Discussionmentioning

confidence: 99%

The influence of CD95L expression on tumor rejection in mice

Igney¹,

Behrens²,

Krammer³

2003

Eur J Immunol

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Many tumors express the death ligand CD95L (CD178, APO-1L, FasL) and can kill activated T cells in vitro. This may enable the tumor cells to suppress anti-tumor immune responses, a phenomenon called "tumor counterattack". Preliminary evidence of tumor counterattack in human tumors exists. However, CD95L-expressing tumors are rapidly rejected in mice. In order to clarify this controversial situation we investigated whether the level or the time point of CD95L expression might be critical factors determining tumor counterattack versus tumor rejection. We generated CD95-resistant tumor cell lines expressing different levels of CD95L (LKC-CD95L). In nude mice the CD95L expression level had no influence on the growth of the CD95L + tumors. In contrast, a CD95L -control tumor cell line (LKC) grew much faster. In addition, we generated a CD95-resistant cell line in which CD95L was induced via the tet system (LKCR-tetCD95L). Induction of CD95L in established tumors in nude and NOD/SCID mice led to rapid rejection of the tumors. Induction of lower CD95L expression levels delayed tumor rejection only marginally. These results demonstrate that rejection of CD95L-expressing tumors in mice is not a result of overexpression and does not depend on the presence of CD95L at the onset of tumor progression.

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Section: Discussionmentioning

confidence: 99%

The influence of CD95L expression on tumor rejection in mice

Igney¹,

Behrens²,

Krammer³

2003

Eur J Immunol

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“…In addition, the altered expression of FasL on tumor cells is able to counterattack CTLs, leading to their apoptosis (78). This mechanism may also activate FasL-mediated activation-induced cell death for CTLs (79). The soluble form of FasL, sFasL, which is Figure 1.…”

Section: Role Of Altered Tumor Surface Antigens and Their Soluble Facmentioning

confidence: 99%

Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

Kim¹,

et al. 2006

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Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-B, prostaglandin E 2 , and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer. (Cancer Res 2006; 66(11): 5527-36)

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“…23,24 FasL is constitutively expressed in the thymus where it plays an important role in the ontogenesis and negative selection of T cells, 2 in activated lymphocytes where it contributes to the establishment of peripheral tolerance, 14 and on various tumor cells to serve as a mechanism of immune evasion by inducing apoptosis of tumor-specific T cells. 44 The pivotal role FasL plays in AICD, 1-3 immune privilege, tolerance to self antigens, 45 and immune evasion by tumors, 46,47 has led to intensive efforts to use the Fas/FasL system as an immunomodulatory approach to induce tolerance to auto and transplantation antigens for the treatment/prevention of autoimmunity and graft rejection.…”

Section: Fasl As a Tolerogenic Agent To Arrest Autoimmunity And Destrmentioning

confidence: 99%

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

Askenasy

Yolcu

Yaniv

et al. 2005

Blood

109

103

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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...

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Immune privilege and FasL: two ways to inactivate effector cytotoxic T lymphocytes by FasL‐expressing cells

Cited by 36 publications

References 36 publications

The influence of CD95L expression on tumor rejection in mice

The influence of CD95L expression on tumor rejection in mice

Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

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

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