Homeostatic regulation of CD8<sup>+</sup> T cells after antigen challenge in the absence of Fas (CD95)

Zimmermann, Christine; Rawiel, Marlies; Blaser, Claudine; Kaufmann, Martina; Pircher, Hanspeter

doi:10.1002/eji.1830261215

Cited by 67 publications

(53 citation statements)

References 52 publications

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“…We found that approximately 30% of specific CTL had reverted to a CD62L high phenotype (indicative of resting T cells) in control mice, in keeping with previously published data [35]. In contrast, in MHC class II -/-and CD40 -/-mice, the frequency of memory CTL (tetramer + CD8 + ) expressing CD62L high was only 3% and 6%, respectively (Fig.…”

Section: Enhanced Activation Of Memory Ctl In the Absence Of Functionsupporting

confidence: 91%

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

Bachmann

Hunziker²,

Zinkernagel³

et al. 2004

Eur J Immunol

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Cytotoxic T lymphocytes (CTL) are essential for control of primary infections by many pathogens and in particular by non-cytopathic viruses. It has been proposed that long-term maintenance of CTL memory and control of lymphocytic choriomeningitis virus (LCMV) is dependent upon the presence of T helper cells and interaction of antigen-presenting cells and CTL via CD40 and its ligand CD40L. However, we demonstrate here that CD40-CD40L interaction maintains CTL memory by induction of virus-specific antibodies. In fact, loss of CTL memory responses and spread of virus in mice lacking CD40 or its ligand is prevented by repetitive therapeutic injections of LCMV-specific antibodies. This indicates that antibodies are essential for long-term control of non-cytopathic virus and to maintain protective memory. Transfer of neutralizing antibodies or induction of antibodies by therapeutic vaccination within weeks after infection may therefore prove beneficial for the treatment of chronic virus infections such as HIV, hepatitis B, and hepatitis C.

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Section: Enhanced Activation Of Memory Ctl In the Absence Of Functionsupporting

confidence: 91%

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

Bachmann

Hunziker²,

Zinkernagel³

et al. 2004

Eur J Immunol

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“…In fact, it was later demonstrated that activated T cells from TNFR2 -/-mice were resistant to Fas-induced apoptosis [25]. It has been shown in mouse models that only CD8 + T cells from Fas knockout mice are resistant to AICD [23], while in vivo studies have given no role [21,22,26], only a limited role [24] or a main role [27][28][29] to Fas-induced apoptosis in the down-modulation of immune responses mediated by CD8 + T cells. Few studies have analyzed this subject in human CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies performed in mice models suggested that while CD4 + T cells were deleted mainly via Fas/FasL, CD8 + T cells were deleted via TNF/ TNFR2 [19,20]. However, other studies did not support such a role for TNF in CD8 + T cell down-modulation [21][22][23][24]. In fact, it was later demonstrated that activated T cells from TNFR2 -/-mice were resistant to Fas-induced apoptosis [25].…”

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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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“…Although in vivo data give clues about the tropism of viruses, MHC dependence (Moskophidis et al, 1994b), and the role of different molecules (Alexander-Miller et al, 1996;Zimmermann et al, 1996), our knowledge of the underlying mechanisms of clonal exhaustion is limited. Zinkernagel et al explain the cause of early clonal exhaustion in terms of total and sudden differentiation (Zinkernagel et al, 1993Zinkernagel, 1996); and argue that in overwhelming infections almost all CTL precursors differentiate into the short-living, nonproliferating effector phenotype and thus they disappear during the second week of immunization [see also Grossman (1986), Grossman et al (1986)].…”

Section: Introductionmentioning

confidence: 99%

“…This choice is supported by the following experimental evidence. First, CD8 + T lymphocytes are susceptible to direct apoptosis induction via binding TNF-α (Zheng et al, 1995;Alexander-Miller et al, 1996) or Fas/FasL interaction (Zimmermann et al, 1996). The innate immunity, especially activated macrophages and NK cells, produce large quantities of TNF-α (Eigler et al, 1997;Horwitz et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Clonal Exhaustion as a Result of Immune Deviation

Keşmir

Boer

2003

Bulletin of Mathematical Biology

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An overwhelming virus infection that spreads within a few days throughout the host can cause deletion of the specific cytotoxic T lymphocytes (CTL). This phenomenon is known as 'clonal exhaustion'. Current explanations for this phenomenon are 'clonal', and consider either the terminal differentiation of the virusspecific CTL to an effector phenotype, or the lack of help and antigen presentation for a specific CTL clone. The virus remains controlled by some other form of immunity in the exhausted state. Candidates are innate immunity (especially NK cells and macrophages) and a T helper type 2 based immune response. Surprisingly, the role of this other form of immunity in causing exhaustion has been ignored so far. Developing a mathematical model, we here investigate the possibility that this inter-clonal immunity is responsible for exhaustion by down regulating the CTL response. The model is based on previously published exhaustion data for Lymphocytic choriomeningitis virus as an in vivo model. We demonstrate that several complicated experiments on clonal exhaustion are consistent with inter-clonal regulation. By interpreting the available data with a mathematical model, we compare this novel mechanism with the mechanisms suggested previously.

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Homeostatic regulation of CD8⁺ T cells after antigen challenge in the absence of Fas (CD95)

Cited by 67 publications

References 52 publications

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

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

Clonal Exhaustion as a Result of Immune Deviation

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Homeostatic regulation of CD8+ T cells after antigen challenge in the absence of Fas (CD95)

Cited by 67 publications

References 52 publications

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

Maintenance of memory CTL responses by T helper cells and CD40‐CD40 ligand: antibodies provide the key

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

Clonal Exhaustion as a Result of Immune Deviation

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Homeostatic regulation of CD8⁺ T cells after antigen challenge in the absence of Fas (CD95)