Soluble human MHC class I molecules induce soluble Fas ligand secretion and trigger apoptosis in activated CD8+ Fas (CD95)+ T lymphocytes

Puppo, Francesco; Contini, Paola; Ghio, Massimo; Brenci, Sabrina; Scudeletti, Marco; Filaci, Gilberto; Ferrone, Soldano; Indiveri, Francesco

doi:10.1093/intimm/12.2.195

Cited by 96 publications

(105 citation statements)

References 54 publications

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“…Like classical sHLA class I antigens (27,28), sHLA-G have been shown by Fournel et al (29) and by one of us (30) to induce apoptosis of activated CD8 + T cells and CD8 + NK cells, although this result has not been confirmed by Hunt (31) who however used recombinant HLA-G in her experiments. Binding to CD8 leads to Fas ligand (L) upregulation, soluble FasL secretion and activated CD8 + cell apoptosis by Fas/sFasL interaction [30].…”

Section: Molecular and Functional Characteristics Of Shla-gmentioning

confidence: 93%

Soluble HLA-G: Are they clinically relevant?

Pistoia¹,

Morandi²,

Wang³

et al. 2007

Seminars in Cancer Biology

161

182

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HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main function in physiological conditions is to abrogate maternal NK cell activity against foetal tissue and to establish immune tolerance at maternal-foetal interface. HLA-G is expressed not only as a membrane bound molecule on the surface of cells, but also as a soluble moiety in body fluids. The major isoforms of HLA-G present in serum are soluble HLA-G1 and HLA-G5 which are generated by shedding or proteolytic cleavage of the membrane bound isoform and by secretion of a soluble isoform, respectively.Here we review the data about soluble HLA-G (sHLA-G) serum levels in different pathological conditions, including immune-mediated disorders, transplantation, and malignancies. In particular, we focus on sHLA-G expression and function in human neuroblastoma, a pediatric tumor, with special emphasis on a novel potential immuno escape mechanism utilized by NB to instruct monocytes to produce and release sHLA-G. Finally, the potential clinical relevance of sHLA-G serum levels is discussed.

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Section: Molecular and Functional Characteristics Of Shla-gmentioning

confidence: 93%

Soluble HLA-G: Are they clinically relevant?

Pistoia¹,

Morandi²,

Wang³

et al. 2007

Seminars in Cancer Biology

161

182

View full text Add to dashboard Cite

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“…[14][15][16] However, we and others reported that sHLA-I molecules lead to activation-induced apoptosis, in vitro, mediated by synthesis and secretion of FasL and the consequent interaction with Fas expressed by allogeneic and autologous T and natural killer (NK) cells. [17][18][19][20][21] Furthermore, nanomolar concentrations of sHLA-I can prevent both alloreactive clones and primary T-cell cultures from recognizing and lysing their targets. 20 It has been reported that sHLA-I molecules bind to CD8 receptors expressed on cytotoxic effector lymphocytes, that is T and NK cells.…”

Section: Introductionmentioning

confidence: 99%

In vivo apoptosis of CD8+ lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand

et al. 2006

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In this study, we show that high serum levels of soluble human leukocyte antigens (HLA) class I molecules (sHLA-I, range: 0.7-1.7 lg/ml) and soluble Fas ligand (FasL, range: 0.4-1.9 ng/ml) are detected in patients with acute myeloid leukemia (AML) at diagnosis, compared with healthy donors (HD) (sHLA-I, range: 0.1-0.6 lg/ml; sFasL, range: 0.1-0.4 ng/ml). Patients' sera were able to induce transcription and secretion of FasL in CD8 þ T cells, followed by apoptosis in vitro; this apoptosis was inhibited by anti-HLA-I-specific monoclonal antibodies, suggesting that sHLA-I is responsible for cell death. These findings closely relate to the in vivo upregulation of FasL transcription observed in peripheral blood (PB) lymphocytes from AML patients; in the same cells, mRNA for the antiapoptotic proteins Bcl-2 and Bcl-x L was downregulated. Interestingly, caspase-8 and caspase-3, both downstream mediators of death receptorinduced apoptosis, were activated in CD8 þ cells of AML patients; one-third of these cells were already apoptotic in vivo, at variance with lymphocytes of HD. These data strongly suggest that in AML, increased levels of sHLA-I molecules may contribute to the elimination of potentially anti-tumor effector cells through a FasL/Fas interaction.

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“…Using long-term CD8 + T cell lines, a main role has been attributed to Fas-induced apoptosis if activated by a complete immunogenic antigen [30], or rather to Bim induction by TCR triggering if activated by a partially agonistic antigen [31]. Other studies have shown that soluble HLA molecules induce apoptosis in polyclonal CD8 + human T cell blasts through release of bioactive FasL into the supernatant [32,33]. No data are available on a possible differential regulation of T cell subsets by APO2L/TRAIL or by CD59 ligation, which have been shown to be implicated in the down-modulation of mixed populations of human T cell blasts [12,14].…”

Section: Introductionmentioning

confidence: 99%

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

et al. 2005

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The mechanisms responsible for the down-modulation of the activation of separated CD4 + or CD8 + human T cell blasts were studied using cells obtained from healthy donors. In the presence of IL-2, human CD8 + T cell blasts were more sensitive than CD4 + T cell blasts to regulation by APO2 ligand/TNF-related apoptosis-inducing ligand (APO2L/TRAIL), while both T cell subsets were equally sensitive to Fas/CD95 regulation. This regulation was defined as inhibition of IL-2-dependent T cell growth in the absence of cell death induction, characterized by cell cycle arrest in G 2 /M. The physiological validity of these observations was corroborated by the demonstration of intracellular FasL and APO2L/TRAIL expression in CD4 + and CD8 + T cell blasts, which were secreted in their bioactive form into the supernatant upon PHA, CD3 or CD59 reactivation. Additionally, the inhibition of IL-2-dependent CD4 + or CD8 + T cell blast growth upon CD3 or CD59 ligation was dependent, at least partially, on FasL and/or APO2L/TRAIL. These data precisely define the role of APO2L/TRAIL in the regulation of human T cell activation. IntroductionT cell tolerance, involving both central and peripheral mechanisms, is a complex process necessary to maintain normal homeostasis and to avoid autoimmunity. Several mechanisms account for the achievement of T cell peripheral tolerance, and defects in just one of them are normally associated with autoimmunity. Among these mechanisms are: (i) the induction of anergy through antigen presentation by non-APC, in the absence of co-stimulation, or by immature APC [1]; (ii) the action of regulatory T cells of CD4 + CD25 + phenotype [2]; and (iii) the termination of T cell immune responses [3].The regulated termination of T cell immune responses is dependent, in turn, on several complex and possibly overlapping cellular and molecular mechanisms. Of these could be cited the increased expression of the negative regulator CTLA-4 [4], IL-2 deprivation as a consequence of antigen exhaustion [5], and activationinduced cell death (AICD) of over-activated T cells [6]. This last mechanism was first reported to be dependent on the Fas/FasL system [7,8]. In fact, lpr and gld mice deficient in functional Fas or FasL expression, respectively [9,10], or humans with similar defects [11] have systemic autoimmune disease characterized by lymphoproliferation. Our group suggested for the first time the participation of APO2 ligand/TNF-related apoptosisinducing ligand (APO2L/TRAIL) and its receptors DR4 and DR5 in the down-regulation of T cell responses [12]. This participation has been confirmed recently in the APO2L/TRAIL knockout mice, which are more susceptible to autoimmune disease induction [13]. We have also found previously that FasL and APO2L/TRAIL are stored inside normal human T cell blasts in cytoplasmic compartments with characteristics of multivesicular bodies [14] and that they are rapidly released into the supernatant in their bioactive form associated with the internal microvesicles upon reactivation [14,15]. H...

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Soluble human MHC class I molecules induce soluble Fas ligand secretion and trigger apoptosis in activated CD8+ Fas (CD95)+ T lymphocytes

Cited by 96 publications

References 54 publications

Soluble HLA-G: Are they clinically relevant?

Soluble HLA-G: Are they clinically relevant?

In vivo apoptosis of CD8+ lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

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