Stem Cells, Vol. 14, No. 6, 632-641,
November 1996
© 1996 AlphaMed Press
Regulation of T Cell Apoptosis via T Cell Receptors and Steroid Receptors
Makoto Iwata,
Yoshiharu Ohoka,
Takeshi Kuwata,
Akiko Asada
Project Research Center, Mitsubishi Kasaei Institute of Life Sciences, Minamiooya, Machida-shi, Tokyo, Japan
Key Words. Apoptosis • T cell • Thymocyte • Positive selection • Glucocorticoid • Protein kinase C • Calcineurin • Retinoic acid
Dr. Makoto Iwata, Project Research Center, Mitsubishi Kasei Institute of Life Sciences 11, Minamiooya, Machida-shi, Tokyo, 194 Japan.
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Abstract
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Less than 5% of immature CD4/CD8 double-positive (DP) thymocytes are positively selected to survive and differentiate into singlepositive CD4 and CD8 T cells, while self-reactive DP thymocytes undergo apoptosis (negative selection). Both positive and negative selection events are active processes that involve signaling through the T cell receptors (TCRs) and through some accessory molecules. The two events differ quantitatively in the strength of the interaction between TCR and peptide/major histocompatibility complex molecules. We established an in vitro model of positive selection that can be analyzed quantitatively. Positive selection is likely to inhibit glucocorticoid-induced apoptosis in DP thymocytes. Proper crosslinking of TCR together with CD4, CD9, or LFA-1 inhibits the death, and its inhibitory activity is mimicked by proper combinations of ionomycin, a calcium ionophore, and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator. The drug concentrations are within narrow ranges, and are lower than those which are required for the proliferation of mature T cells. Transient stimulation with the combinations of ionomycin and PMA induces differentiation and commitment of isolated DP thymocytes to the CD4 or CD8 T cell lineage in suspension cultures. The level of PKC activity appears to determine the lineage to commit. Functional mature T cells are induced from the committed cells upon secondary stimulation. Activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, also appears to be essential for positive selection as well as for the inhibition of glucocorticoid-induced apoptosis. Negative selection and the regulation of mature T cells apoptosis through TCR and steroid receptors are also discussed.
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Introduction
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Regulation of T cell apoptosis is critical for the construction and maintenance of the normal immune system. Developing T cells that express 
ß T cell receptors (TCR) undergo clonal selection events at the CD4/CD8 double-positive (DP) stage in the thymus. Only less than 5% of them are positively selected to survive and differentiate into single-positive (SP) CD4 and CD8 T cells, while the rest of them undergo apoptosis without further differentiation. The latter process includes negative selection that eliminates self-reactive clones. Negative selection is thought to involve strong interactions between the TCR and self-major histocompatibility complex (MHC)-encoded molecule(s) [1]. Indeed, extensive crosslinking of TCR/CD3 complexes induces apoptosis in DP thymocytes [2, 3]. Thymic negative selection does not appear to require Fas (CD95)/Fas ligand (FasL) interactions [4]. DP thymocytes also undergo apoptosis upon exposure to glucocorticoids [3, 5, 6]. However, glucocorticoidinduced apoptosis is inhibited by proper stimulation through TCR/CD3 and costimulation through the coreceptor, CD4 or CD8, and the integrin-leukocyte-function-associated antigen (LFA)-1 (CD11a/CD18) [3, 7]. The antiapoptotic effect of TCR/CD3-and accessorymolecule-mediated stimulation appears to be related to positive selection in the thymus. The anti-apoptotic effect is mimicked by proper combinations of ionomycin, a calcium ionophore, and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator [8, 9]. The combinations induce differentiation and commitment of DP thymocytes to the CD4 or CD8 T cell lineage [10, 11].
A number of murine T cell hybridomas also undergo apoptosis upon stimulation through TCR/CD3 complex or exposure to glucocorticoids. These two apoptotic pathways are mutally antagonistic in these cells [3, 12, 13]. Activation- induced death in T cell hybridomas and peripheral activated T cells is dependent on the Fas/FasL-mediated signaling pathway [4, 14-17]. This mode of cell death may be essential for depletion in the periphery of the self-reactive clones escaped from thymic negative selection.
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Glucocorticoid-Induced Apoptosis in Thymocytes
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An elevation of blood glucocorticoid level by an injection of glucocorticoids or by excessive stress causes thymus involution [5]. The involution is mainly due to apoptosis in cortical DP thymocytes. DP thymocytes are known to undergo apoptosis upon exposure to glucocorticoids while immature CD4/CD8 double-negative cells (precursors of DP thymocytes) or mature SP T cells are much less sensitive to glucocorticoids [18, 19]. Glucocorticoid-induced apoptosis is dependent on the binding of glucocorticoids to cytosolic glucocorticoid hormone receptors (GRs) as it is common in the general steroid effects. The binding of glucocorticoids to GRs induces translocation of the glucocorticoid-GR complex from the cytosol to the nucleus. The complex acts as a translation regulatory factor, inducing, enhancing or repressing the expression of certain genes. Indeed, glucocorticoid-induced apoptosis in thymocytes is inhibited by the inhibitors of mRNA synthesis and protein synthesis [20]. Thus, it is postulated that there is a "death gene(s)" that codes a protein(s) responsible for the induction of apoptosis. Some candidate genes have been cloned, but none have been identified as the death gene. Glucocorticoid-induced death is not dependent on some of the apoptosis-related gene products such as p53, Nur77, or Fas/FasL.
Glucocorticoid-induced apoptosis in murine thymocytes appears to be dependent on PKC-
activation [20]. PKC- is a member of the PKC family including classical Ca2+-dependent (PKC-, -ßI,, -ßII, and -
) novel Ca2+-independent (PKC-
, -, -
(L), -
), and atypical Ca2+-independent (PKC-
, and -
) isozymes [21]. Glucocorticoid-induced thymocyte apoptosis is inhibited by PKC inhibitors. Glucocorticoids induce selective translocation of PKC- from the cytosolic fraction to the particulate fraction of murine thymocytes. The translocation as well as apoptosis induced by glucocorticoids is inhibited by actinomycin D, cycloheximide, or the glucocorticoid antagonist, RU 38486. Thus, glucocorticoid-induced apoptosis in immature thymocytes appears to involve GR-mediated activation of PKC- through de novo synthesis of macromolecules [20]. However, the mechanism of PKC- activation and the subsequent signaling mechanism are not yet clear.
On the role of intracellular Ca2+ level ([Ca2+]i) in glucocorticoid-induced thymocyte apoptosis, conflicting results have been reported in which a sustained increase in [Ca2+]i might initiate the apoptotic pathway, or [Ca2+]i might increase somehow after the cells are committed to apoptosis [22]. We have shown that glucocorticoid-induced apoptosis in thymocytes is inhibited by a proper increase in [Ca2+]i together with proper activation of PKC but not by either one alone [8-10]. In murine T cell hybridomas, glucocorticoid-induced apoptosis is markedly inhibited by the calcium ionophore, ionomycin, alone, and the inhibitory effect is enhanced by the PKC activator, PMA [12].
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Inhibition of Glucocorticoid-Induced Apoptosis in Thymocytes and Thymic Positive Selection
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Positive selection as well as negative selection of thymocytes is an active process that involves signaling through the coreceptor, CD4 or CD8, and the integrin LFA-1 upon direct interactions with thymic stromal cells [23-26]. The differences between these two selection events are considered to be dependent on the differences in affinity or avidity of the TCR to MHC-encoded molecule(s) complexed with self-peptide(s) [1]. Thus, quantitative as well as qualitative differences in signals involved in the events appear to be critical for the fate of each immature clone. Involvement of some signaling molecules, including ZAP-70, calcineurin, PKC, p21ras, mitogen-activated protein (MAP) kinase and Vav, have been suggested to play roles in positive selection [7, 8, 27-32]. However, quantitative analyses of these selection events have been difficult to perform, mainly due to the lack of a proper in vitro model of positive selection. We have recently shown that transient stimulation of DP thymocytes with limited concentrations of ionomycin and PMA induces differentiation and commitment of these cells to the CD4 lineage and the CD8 lineage in suspension culture in the absence of other cell types [10, 11]. DP thymocytes were obtained from TCR transgenic mice with a nonselecting MHC and RAG-2-/- background in which thymocyte development was arrested at the DP stage before positive selection. Secondary stimulation induced mature functional helper and cytolytic T cells from the CD4 lineage-committed and the CD8 lineage-committed cells, respectively [11]. Thus, our system provides an in vitro model of positive selection that would be useful for quantitative analysis of thymic selection.
The combination of ionomycin and PMA was first identified by its ability to mimic the anti-apoptotic effect of TCR-mediated stimulation and costimulation through CD4, CD8, or LFA-1 on glucocorticoid-treated murine thymocytes [3, 7-10]. The peak concentrations of glucocorticoid hormones (0.1 to 1 µM) in the plasma of a normal mouse or rat can induce death in its DP thymocytes in vitro [3, 6], although effective doses of glucocorticoid are affected by the concentrations of glucocorticoid-binding proteins such as transcortin and albumin present in the plasma. Adrenalectomy of mice or injection of an antagonist of glucocorticoids causes a marked increase in the thymus size and the thymocyte number [33, 34], suggesting a possibility that physiological glucocorticoid hormones also induce or enhance apoptosis in DP thymocytes in vivo. Thus, it is conceivable that DP thymocytes which are positively selected should be protected from glucocorticoid-induced death. Glucocorticoid-induced thymocyte apoptosis is significantly inhibited by cross-linking of TCR/CD3 together with CD4, CD8, or LFA-1 at proper levels (not too high and not too low) with specific antibodies [7]. Costimulation through CD4, CD8, or LFA-1 markedly enhances the anti-CD3-induced increase in [Ca2+]i [9]. These cell-surface molecules are known to be involved in positive selection [23-25]. The protective effect of the surface-molecule-mediated stimulation was mimicked by a proper combination of ionomycin and PMA [7-10]. Indeed, the optimal concentrations of ionomycin and PMA to inhibit glucocorticoid-induced apoptosis correspond to those which induce differentiation and lineage commitment of DP thymocytes [10, 11].
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Roles of Calcineurin and PKC in the Signaling Mechanism of Positive Selection
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Positive selection is inhibited by the immuno-suppressants, FK506 and cyclosporin A (CsA) [7, 28-30]. FK506 and CsA are known to inhibit the activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, through binding to FD506-binding protein 12 and cyclophilin, respectively. Thus, the involvement of calcineurin in positive selection has been suggested. Accordingly, FK506 cancels the anti-apoptotic effect of antibodies to TCR/CD3 and CD4, CD8, or LFA-1 (Fig. 1A
) and that of the combination of ionomycin and PMA on glucocorticoid-treated thymocytes (Fig. 1E) [7, 9]. FK506 also cancels the anti-apoptotic effect of ionomycin on glucocorticoid-induced apoptosis in T cell hybridomas [9]. To analyze the role of calcineurin in the anti-apoptotic effect, a T cell hybridoma, BOG8, was transfected with a mutant calcineurin catalytic subunit that shows Ca2+/calmodulin-independent, constitutive phosphatase activity in the cells (Fig.2). The transfectant clones were fairly resistant to glucocorticoid-induced death, indicating that calcineurin activation is indeed involved in the anti-apoptotic effect. Interestingly, as activation-induced death in T cell hybridomas is inhibited by FK 506 and CsA, it has been considered that calcineurin is involved in activation-induced death [35, 36]. However, the transfected clones do not undergo apoptosis but produce interleukin 2 (IL-2) upon stimulation with PMA alone. Apoptosis is induced in these clones by a combination of ionomycin and PMA. Thus, activation-induced death may require a higher level of calcineurin activity than IL-2 production or may require another Ca2+-dependent pathway.
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Figure 1. FK506, Gö 6976, and GF 109203X cancel both the anti-apoptotic effect of antibodies to CD3/LFA-1 and that of ionomycin (IM)/PMA; genistein cancels only the anti-apoptotic effect of the antibodies, not that of IM/PMA. BALB/c thymocytes were cultured with (closed symbols) or without (open symbols) 10 nM dexamethasone (DEX) in the presence of graded concentrations of FK506 (A, E), Gö 6976 (B, F), GF 109203X (C, G) or genistein (D, H) either in the plastic plates that had been coated with a solution containing 1 µg/ml anti-CD3 (145-2C11) and 1 µg/ml anti-CD11a (M17/4.2) (A, B, C) or in the plates containing 0.2 µg/ml IM and 0.2 ng/ml PMA. After 16 h of culture, DNA fragmentation was assessed as previously described [3]. However, the genistein cultures were assessed for DNA fragmentation after 6 h of culture, since genistein by itself induced thymocyte death after 16 h incubation. The data are expressed as means ± SD of triplicate cultures.
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Figure 2. Schematic representation of wild-type calcineurin catalytic subunit (A subunit) and the truncated mutant,  CN. The putative catalytic, calcineurin B subunit (CNB) and immunophilin-binding, calmodulin-binding and autoinhibitory domains are indicated.
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The anti-apoptotic effect of the antibodies on glucocorticoid-treated thymocytes also involves PKC activation. As glucocorticoid-induced death appears to involve PKC- activation, a PKC isozyme(s) other than PKC- may be involved in the protective signal. Indeed, Gö 6976, a specific inhibitor of classical Ca2+-dependent PKC (cPKC) [37], canceled the antiapoptotic effect of antibodies to CD3 and LFA-1 (Fig. 1B
) and that of ionomycin and PMA (Fig. 1F). Similar results were obtained with GF 109203X, a potent inhibitor of cPKC but a weak inhibitor of Ca2+-independent PKC [37] (Figs. 1C and 1G). On the other hand, genistein, an inhibitor of protein tyrosine kinase, canceled the anti-apoptotic effect of antibodies to CD3 and LFA-1 but not that of ionomycin/PMA (Figs. 1D and 1H), indicating that the combination of ionomycin and PMA exerts the antiapoptotic effect bypassing the TCR-proximal signaling pathway including tyrosine kinase activation.
Conflicting results have been reported on the role of PKC in thymic positive selection. A PKC inhibitor, staurosporine, has been shown to inhibit positive selection in fetal thymus organ culture (FTOC) [31], while another PKC inhibitor, Ro 31.8425, failed to inhibit positive selection in reaggregated cultures with thymocytes and thymic stromal cells [29]. Recently, we have found that the cPKC inhibitors, Gö 6976 and GF 109203X, inhibit positive selection in FTOC (unpublished data), indicating that cPKC is indeed involved in positive selection. As MAP kinase has been suggested to be involved in positive selection [32], cPKC activation might involve Raf-1 activation that is known to activate MAP kinase pathways [38].
Ionomycin/PMA-induced lineage commitment in suspension culture is affected by the concentration of PMA. For the survival of thymocytes, the concentration has to be within a narrow range [10, 11]. Within the range, the CD4-lineage commitment required a higher concentration than the CD8-lineage commitment [11]. The concentration range is lower than that required for the proliferation of mature T cells (Fig.3) and SP thymocytes [10]. These results suggest that the level of PKC activity (especially cPKC activity) may determine lineage commitment.
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Figure 3. The concentrations of IM and/or PMA required for the proliferation of splenic T cells are higher than those required for inducing differentiation of double-positive (DP) thymocytes. DP thymocytes undergo differentiation upon treatment with 0.2 µg/ml IM and 0.1 to 0.2 ng/ml PMA [10, 11]. Splenic T cells were obtained from BALB/c mice as previously described [7], suspended (2 x 105 cells/well) and cultured in the presence of graded concentrations of IM and PMA for 30 h. [3H]-thymidine (37 kBq/well) was added for the last 6 h of the culture. The radioactivity bound to DNA was assessed as previously described [3]. The data are expressed as means ± SD of triplicate cultures.
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Glucocorticoid-Induced Death in Mature T Cells
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Glucocorticoid-sensitive and resistant thymocytes as well as mature T cells have almost the same number of GRs per cell, with similar binding properties [19]. Although the majority of murine splenic T cells are resistant to glucocorticoid treatment, a significant population of murine splenic T cells succumbs to apoptotic death by dexa-methasone (DEX), a synthetic glucocorticoid, at the same concentration range that induces apoptosis in thymocytes [39]. Unlike glucocorticoid-induced death in DP thymocytes, cycloheximide failed to inhibit glucocorticoid-induced death in the splenic T cells. Thus, the mechanism of glucocorticoid-induced apoptosis in mature T cells is different from that in immature T cells.
T cell growth factors modulate apoptosis in mature T cells. IL-4 specifically rescues Th2 cells from glucocorticoid-induced apoptosis, whereas IL-2 and IL-1 are ineffective in these cells [40]. On the other hand, IL-2 is the relevant rescue factor of glucocorticoid-treated Th1 cells. PKC activation appears to be involved in the IL-4 or IL-2 dependent protection of Th cells as a PKC inhibitor blocks the protective effect of the lymphokines [40].
Glucocorticoids may be essential cofactors for the superantigen-driven deletion of T cells in vivo. An injection of the Vß8-specific superantigen, staphylococcal enterotoxin B (SEB), into a mouse induces an increase in circulating corticosterone levels, and an administration of RU 38486 abolishes the early deletion of Vß8+ splenic T cells detectable 12 h after the injection of SEB [34].
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TCR/CD3-Mediated Apoptosis in Thymocytes and Negative Selection
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A significant population of immature DP thymocytes undergo apoptosis upon extensive crosslinking of the TCR/CD3 complex by specific antibodies in suspension culture or in FTOC [2, 3]. Negative selection may be based on a similar mechanism. Negative selection as well as activation-induced thymocyte apoptosis in vitro is not blocked by FK506 or CsA [7, 28, 30], although the incomplete deletion of self-reactive thymocytes can be detected several weeks after the start of the injections of CsA [41, 42]. The harmful effect of persistent treatment with CsA on thymic epithelial cells [43] may influence the selection event.
Activation-induced death in T cell hybridomas involves the expression of c-myc [44] and nur77 [45, 46]. Negative selection and activation-induced thymocyte apoptosis appears to be dependent on the Nur77/Nurr1 family of orphan nuclear receptors that belong to the steroid receptor superfamily [47] but are not dependent on p53.
Thymic negative selection appears to be influenced not only by TCR-mediated signals but also by costimulatory signals [48, 49] and the nature and timing of antigens [50]. Anti-CD3-induced apoptosis in thymocytes is augmented by CD28-mediated stimulation in suspension culture [49], whereas full activation of resting mature T cells requires both a TCR/CD3-mediated signal and a costimulatory signal which can be delivered through CD28 upon interaction with its ligands, CD80 (B7-1) and CD 86 (B7-2). Since CD28 is highly expressed on DP thymocytes and its ligands, B7 family members, are expressed on the thymic epithelial and dendritic cells in the medullary regions of the thymus, it is plausible to consider the possibility that CD28 engagement plays a role in the regulation of T cell development. Indeed, the expression of B7 within the thymus medullary epithelium is T cell dependent and correlated with epithelium-mediated depletion of Vß5+ thymocytes [51]. However, conflicting results as to the requirement for B7 in negative selection have also been reported by using in vitro and in vivo models of negative selection [52, 53]. Recently, CD40 ligand (gp39) has been suggested to influence negative selection to some endogenously produced antigens through the regulation of costimulatory molecule expression including B7-2 expression [54].
By making CD30-deficient mice, it has been shown that this glycoprotein is involved in negative selection as well as anti-CD3-induced thymocyte apoptosis in vitro and in vivo [55]. CD30 was originally identified on mononucleated Hodgkin and multinucleated Reed-Sternberg cells in Hodgkin's disease. CD30 shares sequence similarity with other members of the tumor necrosis factor (TNF)/nerve growth factor receptor super family, including p55 and p75 TNF receptors, CD40 and the Fas/Apo-1 antigen. However, the cytoplasmic domain of CD30 does not appear to contain the death domain of Fas or other TNF receptor molecules [56].
The CD45 transmembrane glycoprotein is a protein phosphotyrosine phosphatase. By making mice that completely lack expression of all isoforms of CD45, it has been shown that CD45-null thymocytes are severely impaired in their apoptotic response to crosslinking signals via TCR in FTOC [57]. However, apoptosis is induced normally in these cells by non-TCR-mediated apoptosis-inducing agents such as DEX and anti-Fas antibodies.
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Inhibition of Apoptosis by Glucocorticoids
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Activation-and glucocorticoid-induced apoptotic pathways are mutally antagonistic in T cell hybridomas [3, 12, 13]. Activation-induced death in T cell hybridoma as well as pre-activated mature T cells involves the Fas/FasL interaction [14-17]. Upon activation, T cell hybridomas rapidly express Fas and FasL. Glucocorticoids inhibit the expression of FasL mRNA [58], while TCR/CD3-mediated stimulation activates calcineurin and PKC [9, 12]. Thus, these pathways may antagonize each other in these cells.
Glucocorticoids are also produced in they thymus by non-T cells [59]. The locally produced steroids appear to be essential for the development of double-negative thymocytes to DP thymocytes [60]. Interestingly, it was suggested that glucocorticoids inhibit activation induced thymocyte death in FTOC, and that glucocorticoids are also necessary for survival and maturation of DP thymocytes [59, 60]. However, the role and mechanism of glucocorticoid-dependent inhibition remain to be elucidated. The inhibition of activation-induced apoptosis in thymocytes cannot be observed evidently in suspension cultures [3]. Unlike the activation-induced apoptosis in T cell hybridomas, that in thymocytes does not require Fas/FasL interactions [4]. In our suspension culture system, survival and maturation of DP thymocytes can be induced without adding exogenous glucocorticoids except for minute levels of glucocorticoid hormones in the fetal calf serum [10, 11]. On the other hand, it was also suggested that glucocorticoids participate in some types of negative selection [61].
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Effect of Retinoic Acids on Apoptosis
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Retinoic acid (RA) is known to modulate expression of specific target genes by binding to two classes of intracellular receptors: retinoic acid receptors (RARs) and retinoic X receptors (RXRs), members of the steroid hormone receptor superfamily. All-trans RA, a metabolite of vitamin A, at near-physiological concentrations (0.01 to 1 µM) significantly inhibits the induction of thymocyte apoptosis by co-immobilized antibodies to CD3 and LFA-1 molecules, but enhances glucocorticoid-induced apoptosis. Apoptosis induced in T cell hybridomas by TCR/CD3-mediated stimulation or by the combination of ionomycin and PMA is also inhibited by RA at 0.1 to 10 µM. RA appears to interfere with the apoptotic process at some point after its initiation stage [62]. It has been indicated that 9-cis RA, which binds to RXRs with high affinity in addition to the binding to RARs, inhibits TCR-mediated apoptosis in T cell hybridomas by blocking the expression of FasL following activation [63].
The inhibitory effect of RA may not be solely dependent on the blocking of the FasL expression. It has been reported that antioxidants such as glutathione and N-acetylcysteine can inhibit activation-induced death in T cell hybridomas [64]. As RA is known to have antioxidant potential, it might also inhibit the apoptosis by reducing the oxidative stress.
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Effect of Gonadal Steroids
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An injection of dihydrotestosterone and estradiol in mice deletes the same cortical population of thymocytes as glucocorticoids do. On the other hand, removal of androgens by castration of adult male animals results in significant thymic enlargement and increased thymocyte number. As the receptors for estradiol or dihydrotesterone in the cortical thymocyte population were not found, it has been suggested that the sex steroids bind to other thymic elements, possibly thymic reticular epithelial cells, which may in turn act secondary on cortical thymocytes [65]. Indeed, testosterone and ß-esatradiol fail to affect apoptosis in thymocytes and T cell hybridomas in vitro [3, 66].
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Conclusion
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Glucocorticoid-induced apoptosis in DP thymocytes is inhibited by proper activation of PKC (probably Ca2+-dependent cPKC) and a proper increase in [Ca2+]i that involves calcineurin activation. Since physiological peak levels of endogenous glucocorticoid hormones appear to enhance or induce apoptosis in DP thymocytes in normal mice, positive selection is likely to protect useful clones from glucocorticoid-induced death. Indeed, the anti-apoptotic increase in [Ca2+]i and PKC activity in DP thymocytes followed by incubation without stimuli resulted in the differentiation and commitment of DP thymocytes to the CD4 and CD8 T cell lineage. The level of PKC (probably cPKC) appears to determine the lineage to commit. Secondary stimulation induced functional mature T cells, suggesting that this in vitro system provides an experimental model of positive selection suitable for quantitative as well as qualitative analysis of this event and that the system can be used for obtaining mature self-reactive T cells from normal DP thymocytes.
Negative selection is considered to be based on activation-induced apoptosis, but is influenced by various factors. The Fas/FasL interaction is not necessary in thymic negative selection, but that might be due to possible redundant mechanisms such as the TNF/TNF receptor interaction. The role of glucocorticoids in negative selection and positive selection remains to be elucidated.
The regulation of mature T cells apoptosis is important for controlling the number of activated T cells, depleting self-reactive clones, and maintaining memory T cells. TCR-and steroid-receptor-mediated stimulation are known to influence the regulation, but more studies would be required for elucidating the mechanisms.
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accepted for publication July 5, 1996.
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Abstract
Introduction
