Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the CD8+ T cell response to lymphocytic choriomeningitis virus (LCMV) in mice doubly transgenic for an LCMV-specific TCR and for either bcl-xL or bcl-2. Clonal down-sizing of the anti-viral CD8+ T cell response and the generation of T cell memory was not influenced by constitutive expression of these anti-apoptotic proteins in T cells. Expression of Bcl-xL or Bcl-2 did, however, prevent LCMV peptide-induced peripheral deletion of mature CD8+ T cells in vivo and apoptosis of activated LCMV-specific effector T cells in vitro. The CD8+ T cells "rescued" by Bcl-xL or Bcl-2 from peptide antigen-induced cell death were anergic and this could not be reversed by addition of IL-2 in vitro or by adoptive transfer into antigen-free recipient mice followed by LCMV infection in vivo. Taken together, we show here that 1) Bcl-xL or Bcl-2 are functionally equivalent in their ability to modulate CD8+ T cell survival in vivo, 2) distinct apoptosis signaling pathways exist in CD8+ T cells, one that can be inhibited by Bcl-2 or Bcl-xL and one that cannot be blocked, and 3) apoptosis of CD8+ effector T cells during the declining phase of an immune response is not prevented by constitutive expression of the anti-apoptotic proteins Bcl-xL and Bcl-2.
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PMID:Constitutive expression of Bcl-xL or Bcl-2 prevents peptide antigen-induced T cell deletion but does not influence T cell homeostasis after a viral infection. 952 Oct 66

We have investigated the regulation of adult and cord blood CD45RA+ T cell proliferation and apoptosis to identify factors that may control the naive T cell pool. Cord CD45RA+ T cells were highly susceptible to spontaneous apoptosis as compared with CD45RA+ T cells from adults. Apoptosis was prevented by the addition of IL-2, IL-4, IL-7, and IL-15 which signal via the gamma-chain of the IL-2 receptor. IL-7 prevented the decrease in Bcl-2 and Bcl-xL and induced cell cycling in up to 20% of cord T cells after 8 days, resulting in a threefold increase in cord T cell numbers. However, the expanded cells retained a CD45RA+ CD45RO- phenotype. Similar results were obtained with adult CD45RA+ T cells. IL-7-expanded CD45RA+ RO- T cells expressed CD45RO after stimulation through the TCR. Investigations into the regulation of replicative senescence showed that after 12 days in culture with IL-7, cord blood CD45RA+ T cell proliferation resulted in telomere shortening. Nevertheless, IL-7-expanded cord blood T cells still maintained longer telomeres than unstimulated adult T cells. IL-7 but not IL-2 could directly induce high telomerase activity which probably retarded the rate of telomere shortening in cord blood T cells. These results suggest that proliferation induced by IL-7 may be important for extrathymic expansion of neonatal CD45RA+ T cells and may also contribute to the maintenance of the adult CD45RA+ T cell pool.
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PMID:IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire. 983 71

Mice lacking the common cytokine receptor gamma-chain (gamma c) exhibit severely compromised T cell development, with diminished Bcl-2 expression in mature (CD4+ or CD8+) thymocytes and peripheral T cells. Enforced expression of Bcl-2 in these mice partially rescued alpha beta T cell development but not gamma delta T cell development. Transgenic expression of the OVA-specific DO11.10 (DO10) TCR also could modestly increase thymocyte numbers, and T cells expressing the transgenic TCR (KJ1-26+ T cells) were found in the periphery. Interestingly, the presence of KJ1-26+ T cells was dependent on the MHC background and was seen in the moderate affinity H-2d/d background but not in the higher affinity H-2d/b background in gamma c-deficient mice. In contrast, KJ1-26+ T cells exist in the periphery in both the H-2d/d and H-2d/b backgrounds in DO10 transgenic gamma c wild-type mice. These results suggest that the importance of gamma c-dependent signals for T cell development differs depending on the affinity of TCR for MHC. Moreover, enforced expression of Bcl-2 had a much greater effect on the development of gamma c-deficient T cells expressing the DO10 TCR in the high affinity H-2d/b background than in the H-2d/d background, suggesting that gamma c-dependent Bcl-2 expression influences T cell development in a TCR/MHC-dependent manner.
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PMID:Role of Bcl-2 in alpha beta T cell development in mice deficient in the common cytokine receptor gamma-chain: the requirement for Bcl-2 differs depending on the TCR/MHC affinity. 991 99

TCR gamma delta+ cells are enriched in the intestine mucosa and constitute approximately half of the intestinal intraepithelial lymphocytes (iIEL) in mice. They are likely activated by self and foreign Ags in situ, but little is known about how the activated gamma delta iIEL are regulated. In the iIEL compartment, IL-2 is produced by activated TCR alpha beta+ iIEL, and IL-15 message is detected in iIEL and in the epithelial cells. We found surface expression of IL-2 as well as IL-15Rs on activated gamma delta iIEL, and examined the effects of IL-2 and IL-15 on the survival and death of gamma delta iIEL during secondary stimulation through TCR. We found that both cytokines supported growth of the restimulated gamma delta iIEL, but exerted different effects on their survival. A significant higher number of live cells were recovered from the gamma delta iIEL cultures restimulated in IL-15 than in IL-2. Quantitation of apoptotic cells showed more cell death in the IL-2 group than in the IL-15 group. The cell death was associated with restimulation through TCR and was not caused by insufficient growth factor, thus representing activation-induced cell death. Western blot analyses found no difference in the levels of Bcl-2 and Bax proteins between the two groups. However, the level of Bcl-xL protein diminished with time in the IL-2 group whereas the level was sustained in the IL-15 group, which may contribute to the pro-survival effect of IL-15. These results demonstrated that the survival of activated gamma delta iIEL is differentially regulated by IL-2 and IL-15.
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PMID:Differential effects of IL-2 and IL-15 on the death and survival of activated TCR gamma delta+ intestinal intraepithelial lymphocytes. 997 56

The differentiation process from CD4-CD8- double-negative (DN) thymocytes to CD4+CD8+ double-positive (DP) stage is accompanied by vigorous proliferation. The resulting DP cells contain a sizable proportion of large cycling cells, but most DP cells are small resting cells. To explore the molecular mechanisms which regulate cell proliferation of DP thymocytes prior to further development, we used TCR-transgenic (Tg) mice with non-selecting MHC (Tg-Neut), which contain almost exclusively DP thymocytes that are not subject to either positive or negative selection. In Tg-Neut, the thymus contained DP cells of relatively large size, which showed higher extracellular signal-regulated kinase activity and enhanced responsiveness to mitogen compared to small DP cells. This indicates that all the large DP cells in the thymus are not positively selected and that they possess proliferative potential. When Tg-Neut mice were backcrossed with CD45 knockout mice (CD454-/- Tg-Neut), the thymus showed an increase of large DP cells and cycling cells, but a decrease of apoptotic cells. Furthermore, Bcl-2 expression and Jun N-terminal kinase activity, which are associated with resistance to apoptosis, were enhanced. These observations suggest that thymocyte proliferation in the DP stage is suppressed by a CD45-related process with regulation of mitogen-activated protein kinase and Bcl-2 unless DP cells receive TCR-mediated signals.
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PMID:CD45 can act as a negative regulator for the transition from early to late CD4+ CD8+ thymocytes. 1005 Jun 77

We previously isolated a CD4 ligand glycoprotein, gp17, from human seminal plasma; this glycoprotein is identical with gross cystic disease fluid protein-15 (GCDFP-15), a factor specifically secreted from primary and secondary breast tumors. The function of gp17/GCDFP-15 in physiological as well as in pathological conditions has remained elusive thus far. As a follow up to our previous findings that gp17 binds to CD4 with high affinity and interferes with both HIV-1 gp120 binding to CD4 and syncytium formation, we investigated whether gp17 could affect the T lymphocyte apoptosis induced by a separate ligation of CD4 and TCR. We show here that gp17/GCDFP-15 is in fact a strong and specific inhibitor of the T lymphocyte programmed cell death induced by CD4 cross-linking and subsequent TCR activation. The antiapoptotic effect observed in the presence of gp17 correlates with a moderate up-regulation of Bcl-2 expression in treated cells. The presence of gp17 also prevents the down-modulation of Bcl-2 expression in Bcl-2bright CD4+ T cells that is caused by the triggering of apoptosis. Our results suggest that gp17 may represent a new immunomodulatory CD4 binding factor playing a role in host defense against infections and tumors.
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PMID:Potent inhibition of CD4/TCR-mediated T cell apoptosis by a CD4-binding glycoprotein secreted from breast tumor and seminal vesicle cells. 1007 5

The regulation of apoptosis in mature CD4+ or CD8+ alphabeta+ T cells has been well studied. How the survival and death is regulated in peripheral CD4-CD8- (double negative, DN) alphabeta+ T cells remains unknown. Recent studies suggest that peripheral DN T cells may play an important role in the regulation of the immune responses mediated by CD4+ or CD8+ T cells. Here, we used immunosuppressive DN T cell clones to elucidate the mechanisms involved in the regulation of death and survival of alphabeta+ DN T cells. The DN T cell clones were generated from the spleen cells of 2C transgenic mice, which express the transgenic TCR specific for Ld and permanently accepted Ld+ skin allografts after pretransplant infusion of Ld+ lymphocytes. We report that 1) the mature DN T cells are highly resistant to TCR cross-linking-induced apoptosis in the presence of exogenous IL-4; 2) Fas/Fas-ligand and TNF-alpha/TNFR pathways do not play an apparent role in regulating apoptosis in DN T cells; 3) the DN T cells constitutively express a high level of Bcl-xL, but not Bcl-2; 4) both Bcl-xL and Bcl-2 are up-regulated following TCR-cross-linking; and 5) IL-4 stimulation significantly up-regulates Bcl-xL and c-Jun expression and leads to mitogen-activated protein kinase phosphorylation in DN T cells, which may contribute to the resistance to apoptosis in these T cells. Taken together, these results provide us with an insight into how mature DN T cells resist activation-induced apoptosis to provide a long-term suppressor function in vivo.
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PMID:Regulation of apoptosis in mature alphabeta+CD4-CD8- antigen-specific suppressor T cell clones. 1022 21

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.
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PMID:CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. 1038 16

Memory T cells respond in several functionally different ways from naive T cells and thus function as efficient effector cells. In this study we showed that primed T cells were more resistant to Fas-mediated activation-induced cell death (AICD) than naive T cells using OVA-specific TCR transgenic DO10 mice and Fas-deficient DO10 lpr/lpr mice. We found that apoptosis was efficiently induced in activated naive T cells at 48 and 72 h after Ag restimulation (OVA peptide; 0.3 and 3 microM), whereas apoptosis was not significantly increased in activated primed T cells at 24-72 h after Ag restimulation. We further showed that the resistance to AICD in primed T cells was due to the decreased sensitivity to apoptosis induced by Fas-mediated signals, but TCR-mediated signaling equally activated both naive and primed T cells to induce Fas and Fas ligand expressions. Furthermore, we demonstrated that primed T cells expressed higher levels of Fas-associated death domain-like IL-1beta-converting enzyme inhibitory protein (FLIP), an inhibitor of Fas-mediated apoptosis, at 24-48 h after Ag restimulation than naive T cells. In addition, Bcl-2 expression was equally observed between activated naive and primed T cells after Ag restimulation. Thus, these results indicate that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period.
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PMID:Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells. 1041 29

IL-2-dependent, activation-induced T cell death (AICD) plays an important role in peripheral tolerance. Using CD8+ TCR-transgenic lymphocytes (2C), we investigated the mechanisms by which IL-2 prepares CD8+ T cells for AICD. We found that both Fas and TNFR death pathways mediate the AICD of 2C cells. Neutralizing IL-2, IL-2R alpha, or IL-2R beta inhibited AICD. In contrast, blocking the common cytokine receptor gamma-chain (gamma c) prevented Bcl-2 induction and augmented AICD. IL-2 up-regulated Fas ligand (FasL) and down-regulated gamma c expression on activated 2C cells in vitro and in vivo. Adult IL-2 gene-knockout mice displayed exaggerated gamma c expression on their CD8+, but not on their CD4+, T cells. IL-4, IL-7, and IL-15, which do not promote AICD, did not influence FasL or gamma c expression. These data provide evidence that IL-2 prepares CD8+ T lymphocytes for AICD by at least two mechanisms: 1) by up-regulating a pro-apoptotic molecule, FasL, and 2) by down-regulating a survival molecule, gamma c.
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PMID:The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death. 1047 79


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