Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia

Clonal T-cell expansion in patients with T-large-granular lymphocyte (LGL) leukemia occurs by an undefined mechanism that may be related to Fas apoptosis resistance. Here, we demonstrate polarized expansion of CD8(+) terminal-memory differentiation in such patients, as demonstrated by CD45RA expression and absence of CD62L expression, suggesting repeated stimulation by antigen in vivo. Elimination of antigen-stimulated T cells normally occurs through Fas-mediated apoptosis. We show that cells from LGL leukemia patients express increased levels of c-FLIP and display resistance to Fas-mediated apoptosis and abridged recruitment of proteins that comprise the death-inducing signaling complex (DISC), including the Fas-associated protein with death-domain (FADD) and caspase-8. Exposure to interleukin-2 (IL-2) for only 24 hours sensitized leukemic LGL to Fas-mediated apoptosis with enhanced formation of the DISC, and increased caspase-8 and caspase-3 activities. We observed dysregulation of c-FLIP by IL-2 in leukemic LGL, suggesting a role in Fas resistance. Our results demonstrate that expanded T cells in patients with LGL leukemia display both functional and phenotypic characteristics of prior antigen activation in vivo and display reduced capacity for Fas-mediated DISC formation.     

Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists

Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T-cell-mediated immunity associated with T-cell apoptosis. We report here that CD4+ and CD8+ T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)-mediated death induced either by an agonistic anti-Fas antibody or by the physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis factor alpha-induced death. CD4+ and CD8+ T-cell apoptosis induced by Fas ligation was enhanced by inhibitors of protein synthesis and was prevented either by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas- mediated apoptosis could also be prevented in a CD4+ or CD8+ T-cell- type manner (1) by several protease antagonists, suggesting the involvement of the interleukin-1beta (IL-1beta)-converting enzyme (ICE)- related cysteine protease in CD4+ T-cell death and of both a CPP32- related cysteine protease and a calpain protease in CD8+ T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL-10, that exerted their effects through a mechanism that required de novo protein synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4+ T cells from HIV-infected persons involved a Fas-mediated death process, whereas TCR stimulation of CD8+ T cells led to a different Fas-independent death process. These findings suggest that Fas-mediated T-cell death is involved in acquired immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated signaling may represent a target for new therapeutic strategies aimed at the prevention of CD4+ T-cell death in AIDS.     

Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation.

Signaling via the T-cell receptor complex is necessary but not sufficient to induce antigen-specific T lymphocytes to expand clonally. To proliferate, T cells must receive one or more costimulatory signals provided by antigen presenting cells (APCs). One such critical costimulatory signal is delivered by the CD28/CTLA-4 counterreceptor, B7, expressed on APCs. B7 costimulation induces CD28 signaling, resulting in interleukin 2 (IL-2) secretion, and T-cell proliferation. Conversely, T-cell receptor signaling in the absence of B7 costimulation results in induction of antigen-specific tolerance. Here, we show that activated human B lymphocytes express two additional CTLA-4 counterreceptors also capable of providing T-cell costimulation. At 24 hr postactivation, B cells express a CTLA-4 counterreceptor not recognized by anti-B7 or -BB-1 monoclonal antibodies (mAbs), which induces detectable IL-2 secretion and T-cell proliferation. At 48 and 72 hr postactivation, B cells express both B7 and a third CTLA-4 counterreceptor identified by the anti-BB-1 mAb. BB-1 appears to be a molecule distinct from B7 by its expression on B7- cells and its capacity to induce T cells to proliferate without significant accumulation of IL-2. As observed for B7, costimulatory signals mediated by these alternative CTLA-4/CD28 counterreceptors are likely to be essential for generation of an immune response and their absence may result in antigen-specific tolerance. We propose the following terminology for these CTLA-4 counterreceptors: (i) B7, B7-1; (ii) early CTLA-4 binding counterreceptor, B7-2; and (iii) BB-1, B7-3.     

B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2.

Occupancy of the T-cell receptor complex does not appear to be a sufficient stimulus to induce a T-cell-mediated immune response. Increasing evidence suggests that cognate cell-cell interaction between an activated T cell and an antigen-presenting cell may provide such a stimulus. A candidate T-cell surface molecule for this costimulatory signal is the T-cell-restricted CD28 antigen. Following crosslinking with anti-CD28 mAb, suboptimally stimulated CD28+ T cells show increased proliferation and markedly increased secretion of a subset of lymphokines. Recently, the B-cell surface activation antigen B7 was shown to be a natural ligand for the CD28 molecule, and both B7 and CD28 are members of the immunoglobulin superfamily. Here we report that B7-transfected CHO cells can induce suboptimally activated CD28+ T cells to proliferate and secrete high levels of interleukin 2. The response is identical whether T cells are submitogenically stimulated with either phorbol myristate acetate or anti-CD3 to activate the T cells. This response is specific and can be totally abrogated with anti-B7 monoclonal antibody. As has previously been observed for anti-CD28 monoclonal antibody, B7 ligation induced secretion of interleukin 2 but not interleukin 4. We have previously demonstrated that B7 expression is restricted to activated B lymphocytes and interferon gamma-activated monocytes. Since these two cellular populations are involved in antigen presentation as well as cognate interaction with T lymphocytes, B7 is likely to represent a central constimulatory signal that is capable of amplifying an immune response.     

Responding naive T cells differ in their sensitivity to Fas engagement: early death of many T cells is compensated by costimulation of surviving T cells

Engagement of Fas (CD95) induces death of activated T cells but can also potentiate T-cell response to CD3 ligation. Yet, the effects of Fas-mediated signals on activation of naive T cells have remained controversial. We followed naive T cells responding under Fas ligation. Ligation of Fas simultaneously with activation by antigen-bearing dendritic cells promoted early death in half of the responding naive murine CD4 T cells. Surprisingly, it simultaneously accelerated cell division and interferon-gamma (IFN-gamma) production among surviving T cells. These cells developed quickly an activation-associated phenotype (CD44(hi), CD62L(lo)), responded vigorously to antigen rechallenge, were partially resistant to subsequent induction of cell death via Fas, and were long-lived in vivo. Compared with cells becoming apoptotic, the surviving cells expressed lower levels of Fas and higher levels of T-cell receptor (TCR), CD4, and interleukin-2 receptor (IL-2R). Their survival was associated with expression of antiapoptotic cellular FLICE-inhibitory protein (c-FLIP), Bcl-X(L), and Bcl-2. Thus, at the time of T-cell activation there is a subtle balance in the effects of Fas ligation that differs on a cell-to-cell basis. Factors that predict cell survival include expression levels of Fas, TCR, CD4, and IL-2R. Early death of some cells and a pronounced response of the surviving cells suggest that Fas ligation can both up- and down-regulate a primary T-cell response.     

Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis

Our recent studies have shown that immune cell-produced complement provides costimulatory and survival signals to naive CD4(+) T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3(-/-) APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell-expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.     

Homeostatic control of T-cell generation in neonates

T cells are produced through 2 mechanisms, thymopoiesis and proliferative expansion of postthymic T cells. Thymic output generates diversity of the pool, and proliferation achieves optimal clonal size of each individual T cell. To determine the contribution of these 2 mechanisms to the formation of the initial T-cell repertoire, we examined neonates of 30 to 40 weeks' gestation. Peripheral T cells were in a state of high proliferative turnover. In premature infants, 10% of T cells were dividing; the proliferation rates then declined but were still elevated in mature newborns. Throughout the third trimester, concentrations of T-cell-receptor excision circles (TRECs) were 10 per 100 T cells. Stability of TREC frequencies throughout the period of repertoire generation suggested strict regulation of clonal size to approximately 10 to 20 cells. Neonatal naive CD4+ and CD8+ T cells were explicitly responsive to IL-7; growth-promoting properties of IL-15 were selective for newborn CD8+ T cells. Neonatal T cells expressed telomerase and, in spite of the high turnover, built up a telomeric reserve. Thus, proliferative expansion, facilitated by increased cytokine responsiveness, and thymopoiesis complement each other as mechanisms of T-cell production in neonates. Maintaining optimal clonal size instead of filling the space in a lymphopenic host appears to regulate homeostatic T-cell proliferation during fetal development.     

Anti-Fas (CD95/Apo-I) autoantibodies and soluble Fas levels concur in T cell depletion in HIV type 1 infection

Deregulation of the Fas/FasL pathway in activated T cells is suspected to contribute to the abnormal apoptosis that drives their progressive depletion during HIV-1 infection. However, the role of serum soluble Fas (sFas) is unclear. Here we investigated both sFas and anti-Fas IgG levels in a cohort of 227 HIV-1-infected patients with respect to their T cell apoptosis. By using optimized ELISAs, we found that serum titers of sFas and anti-Fas were linearly correlated in 17 severely lymphopenic subjects as compared with other patients grouped in relation to their single expression of anti-Fas and sFas, or with double-negative control patients. Cytofluorimetric measurement of the subdiploid DNA-containing cell population by both PI and TUNEL revealed an increased occurrence of cell death in vitro, in particular in patients with elevations of sFas. We also found that fresh CD4(+) cells from these patients showed high levels of both caspase 3 (CPP32) and its molecular targets, namely PARP and CK18. In addition, their in vitro proliferative rate was inhibited by sFas, in particular in patients with undetectable levels of the soluble receptor in vivo as well as in normal donors. In these subjects the Fas-related caspase 8 (FLICE) was significantly increased in cells treated with the recombinant Fas. These results support the contention that functionally exhausted T cells may undergo apoptosis in response to the persistent in vivo stimulation by sFas. This may elucidate the described occurrence of enhanced cell death in advanced HIV-1 infection in association with serum elevations of the soluble receptor.     

Epstein-Barr virus induces Fas (CD95) in T cells and Fas ligand in B cells leading to T-cell apoptosis.

Epstein-Barr virus (EBV) acute infectious mononucleosis (AIM) is characterized by transient immunosuppression in vivo and increased T-cell apoptosis after ex vivo culture of AIM peripheral blood mononuclear cells. We undertook experiments to test whether EBV or purified virion envelope glycoprotein gp350 could contribute to Fas-mediated T-cell apoptosis. Our in vitro results indicate that EBV increased Fas expression in CD4(+) T cells and Fas ligand (FasL) expression in B cells and macrophages. Purified gp350 was also shown to significantly increase CD95 expression in CD4(+) T cells. When T-cell CD95 was cross-linked, EBV-stimulated T cells underwent apoptosis. The induction of T-cell CD95 by EBV followed by CD95 cross-linking with anti-CD95 monoclonal antibody resulted in a loss in the number of T cells responding to the T-cell mitogens, anti-CD3 antibody, and interleukin-2. These results indicate that, in addition to serving as a principal ligand for the attachment of virus to target cells, gp350 may also act as an immunomodulatory molecule that promotes T-cell apoptosis.     

Interleukin-2-deficient mice develop colitis in the absence of CD28 costimulation

The intestinal lamina propria contains lymphocytes that are chronically activated by exposure to luminal antigens. Dysregulation of these cells is thought to be central to the pathogenesis of bowel inflammation in experimental models of inflammatory bowel disease. CD28 signals on peripheral T cells provide important costimulatory signals that enhance T-cell proliferation and activation responses to antigens. However, the role of CD28 signals in lamina propria T cells or models of inflammatory bowel disease have not been determined. Accordingly, we examined T lymphocyte activation and proliferation in CD28-deficient (CD28-/-) mice to examine the in vivo roles of CD28 signals in lamina propria T-cell homeostasis. We further generated CD28-/- interleukin (IL)-2-/- double mutant mice to assess the role of CD28 signals in supporting the spontaneously activated and pathogenic T cells that accumulate in IL-2-/- mice. CD28-/- lamina propria T cells displayed reduced activation markers, but were present in normal numbers and proliferated normally. IL-2-/- lymphocytes expressed high levels of bcl-xL, whereas CD28-/- IL-2-/- cells had substantially less bcl-xL. However, lymphadenopathy and ulcerative colitis-like disease occurred in both IL-2-/- and CD28-/- IL-2-/- mice. Thus, CD28 provides a functional costimulatory signal to lamina propria T cells but is not required for homeostasis of these cells. In addition, neither CD28 nor bcl-xL appears to be required for the spontaneous accumulation of T cells in IL-2-/- mice. This suggests that other costimulatory molecules or T-cell receptor ligation alone drive lymphocyte expansion in IL-2-deficient mice.     

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4(+) T cells, CD4XL-induced sensitization for apoptosis was observed in CD8(+) T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell-cell contact with FasL(+) CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4(+) T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.     

Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities

Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDSs), and inhibition by immunosuppression may account for the success of this treatment in some patients. We examined bone marrow and peripheral blood of 25 patients with chromosomal abnormalities associated with MDS (monosomy 7, trisomy 8, and 5q-) for evidence of apoptosis. When fresh bone marrow was examined, the number of apoptotic and Fas-expressing CD34 cells was increased in patients with trisomy 8, but decreased in monosomy 7, as compared with healthy control donor marrow. Fas expression was increased in the trisomy 8 cells and decreased in the monosomy 7 cells when compared with normal cells from the same patient. Trisomy 8 cells were more likely to express activated caspase-3 than were normal cells. For bone marrow cells cultured with Fas agonist or Fas antagonist, the percentage of cells with trisomy 8 was significantly decreased in most cases after Fas receptor triggering and increased by Fas ligand (Fas-L) antagonist (P < 0.01), suggesting increased Fas susceptibility of cells with trisomy 8. No such changes were seen in cultures of cells with 5q- or monosomy 7. Fas antagonist facilitated the expansion of cells with trisomy 8 only. Cells with trisomy 8 appear to be more susceptible to Fas-mediated apoptosis. Clinical data demonstrating the responsiveness of some patients with trisomy 8 to anti-thymocyte globulin (ATG) and cyclosporine (CsA) would favor an active role of the immune system in this syndrome.     

CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells

Cytotoxic function of CD4+ Th1 cells is mediated by Fas (CD95, APO-1) and its ligand (Fas ligand). Recent studies using nontransformed B cells and the Ramos Burkitt's lymphoma (BL) B-cell line cells show that CD40 ligation at the B-cell surface by activated, CD40 ligand (CD40L)- bearing, CD4+ T cells upregulates Fas expression on B cells and primes B cells for Fas-mediated death signals. In this work, we examine whether this CD4+ T-cell-dependent molecular pathway for Fas upregulation and B-cell apoptosis reflects a peculiarity of the Ramos B- cell line or is applicable to other Burkitt's tumors as well. In 5 of the 6 Epstein-Barr virus-negative BL cell lines examined, the cells constitutively express undetectable or low levels of Fas and are resistant to Fas-mediated signals induced by monoclonal anti-Fas antibody. All 6 of the BL cell line B cells upregulate Fas in response to CD40 ligation, and in 4 of the cases they become sensitive to Fas- mediated death signals. In one BL cell line, the cells are constitutively sensitive to Fas-mediated cytolysis and are unaffected by CD40 signals. Next, we applied these immunologic manipulations to cells from a refractory clinical sample and observed that the tumor cells could be induced to express Fas and undergo apoptosis in our system. These results establish CD4+ T cells and the Fas-Fas ligand system as important immune regulators of Burkitt's lymphoma B cells and indicate that the susceptibility of tumor cells to Fas-mediated death signals can be modulated by specific activation events at the cell surface.     

Fas ligation induces IL-1beta-dependent maturation and IL-1beta-independent survival of dendritic cells: different roles of ERK and NF-kappaB signaling pathways

The mechanisms that underpin the intriguing capacity of Fas ligation on dendritic cells (DCs) to induce maturation and activation, rather than apoptosis, remain unclear. In the present study we confirm that Fas signaling induces both phenotypic and functional maturation of murine DCs, and we demonstrate that phenotypic maturation is associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, activation of caspase-1, and secretion of interleukin-beta (IL-1beta). Specific inhibition of ERK1/2 diminished Fas ligation-induced caspase-1 activation, IL-1beta secretion, and ensuing up-regulation of developmental markers, whereas treatment with neutralizing anti-IL-1beta antibody abrogated phenotypic and functional maturation, indicating that IL-1beta mediates Fas ligation-induced DC maturation in an autocrine manner. NF-kappaB activation was responsible for maintaining DC viability after Fas ligation. Inhibiting NF-kappaB did not affect either IL-1beta secretion or phenotypic maturation but rather sensitized DCs to Fas-mediated apoptosis. In conclusion, positive signals originating from Fas are transduced through at least 2 different intracellular pathways in DCs, promoting not only survival but also an increase in maturation that correlates with increased antigen-presentation capability.     

Priming CD8+ T cells with dendritic cells matured using TLR4 and TLR7/8 ligands together enhances generation of CD8+ T cells retaining CD28

TLRs expressed on dendritic cells (DCs) differentially activate DCs when activated alone or in combination, inducing distinct cytokines and costimulatory molecules that influence T-cell responses. Defining the requirements of DCs to program T cells during priming to become memory rather than effector cells could enhance vaccine development. We used an in vitro system to assess the influence of DC maturation signals on priming naive human CD8+ T cells. Maturation of DCs with lipopolysaccharide (LPS; TLR4) concurrently with R848 (TLR7/8) induced a heterogeneous population of DCs that produced high levels of IL12 p70. Compared with DCs matured with LPS or R848 alone, the DC population matured with both adjuvants primed CD8+ T-cell responses containing an increased proportion of antigen-specific T cells retaining CD28 expression. Priming with a homogenous subpopulation of LPS/R848-matured DCs that were CD83(Hi)/CD80+/CD86+ reduced this CD28+ subpopulation and induced T cells with an effector cytokine signature, whereas priming with the less mature subpopulations of DCs resulted in minimal T-cell expansion. These results suggest that TLR4 and TLR7/8 signals together induce DCs with fully mature and less mature phenotypes that are both required to more efficiently prime CD8+ T cells with qualities associated with memory T cells.     

Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection

After acute infection Epstein-Barr virus (EBV)-specific memory CD8+ T cells exit cell cycle, and a proportion of these antigen-experienced cells re-express CD45RA (CD45 which predominantly express exon A). However, the signals involved are not known. We investigated the roles of interleukin 15 (IL-15) and interferon-alpha/beta (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8+ T-cell memory. We show that IFN-I (but not IL-15) allows activated EBV-specific CD8+ T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I) induced "homeostatic" proliferation and CD45RA re-expression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA re-expression in activated EBV-specific CD8+ T cells. After T-cell receptor (TCR) activation freshly isolated CD45RA+ antigen-experienced CD8+ T cells show poor proliferative activity but are highly cytotoxic and secrete IFN-gamma efficiently. This suggests functional reprogramming toward effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8+ T cells that re-express CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.     

Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines,interleukin-8 and monocyte chemoattractant protein-1

BACKGROUND: To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion. METHODS AND RESULTS: After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression. CONCLUSION: In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.     

Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.