Treatment-Resistant Expansion of CD8+CD28− Cells in Pediatric HIV Infection
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CD28, a cell-surface molecule expressed by T cells, delivers costimulatory signals during the activation of T cells by Ag. Stimulation of CD28 induces its association with phosphatidylinositol 3'-kinase (PI3-K), raising the possibility that PI3-K plays a critical role in CD28 signaling. We find, however, that wortmannin, a potent inhibitor of PI3-K, does not block CD28-mediated costimulation of Jurkat (a human T cell line) or of murine CD4+ T cells. To address further the role of PI3-K in CD28-mediated signaling, we expressed mutant murine CD28 molecules in Jurkat cells. Mutation of Tyr 170 of murine CD28 to Phe abrogates the association of murine CD28 with PI3-K but does not affect the ability of murine CD28 to augment IL-2 production by Jurkat cells in response to the combination of ionomycin and PMA. Conversely, a mutant of murine CD28 that has a Tyr at position 170 but has Phe substitutions at the remaining three cytoplasmic tyrosines retains the ability to associate with PI3-K and has an impaired ability to deliver a costimulus that augments IL-2 production. CD28, therefore, can deliver costimulatory signals independently of its interaction with PI3-K, and association with PI3-K is insufficient to mediate the full effector function of CD28. Optimal signaling by CD28 requires the integrity of one or more of the carboxyl-terminal three Tyr residues.
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Abstract The costimulatory receptor CD28 is important in the development of both Th1 and Th2 responses. To further assess the requirement for CD28 in the development of Th1 and Th2 responses, we analyzed the ability of T cells from wild-type or CD28- mice to secrete cytokines in MLRs with B lymphomas. We find that in the absence of added IL-12, B lymphomas expressing the alternate costimulatory ligand 4-1BBL can support the production of IL-2 and IL-4 but little detectable IFN-gamma by allogeneic CD28+ and CD28- T cells. IL-4 production by CD28+ or CD28- T cells responding to B7(low) B lymphomas was abrogated by blocking 4-1BB ligand-4-1BB interaction. When APC express high levels of B7 family molecules as well as 4-1BBL, soluble 4-1BB inhibits IL-4 production by CD28- but not by CD28+ cells. Addition of IL-12 to the CD28- MLRs results in increased production of IFN-gamma and decreased amounts of IL-2 and IL-4. Thus, both Th1 and Th2 responses can develop in the complete absence of a signal through the CD28 molecule. CD28+ and CD28- T cells differed, however, with respect to the effect of IL-12 on IL-4 production. IL-12 severely curtailed the amount of IL-4 produced in the CD28- T cell cultures but had a less profound effect on the level of IL-4 produced in the CD28+ cultures, suggesting that a strong signal through the CD28 molecule prevents down-regulation of IL-4 production by IL-12.
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To investigate the relationship between expression of Fas-FasL and apoptosis of peripheral blood CD8+CD28-and CD8+CD28+T lymphocytes in patients with systemic lupus erythematosus(SLE),the rates of Fas-FasL expression and apoptosis of CD8+CD28-and CD8+CD28+ T cells were measured by three antibodies labeling flow cytometry(FCM) analysis in 22 active cases,18 inactive cases of SLE and 20 controls.The results showed that:(1)Compared to controls and inactive SLE,apoptosis rates of CD8+ T cells was significantly higher in active SLE group(P0.05),and the expression of Fas in CD8+CD28-T cells and FasL in CD8+CD28+T cells were higher in active SLE group(P0.05).The expression rate of Fas of CD8+CD28+ T cells in SLE patients was featured by the fact that active SLE group inactive SLE groupcontrol group,and there was a significant difference in statistics in these 3 groups(P0.05).(2) The activity of SLE was positively correlated with the apoptosis rate of CD8+T cells,but there was no correlation with expression of Fas、FasL in CD8+CD28-and CD8+CD28+ T cells.(3) The expression of Fas、FasL were correlated with apoptosis,and expression of Fas was significant correlated with expression of FasL in CD8+CD28+ T cells.The expression of Fas was not significantly correlated with expression of FasL in CD8+CD28-Tcells.It is concluded that the apoptotic rate of the peripheral blood CD8+T cells is abnormally increased and the activity of SLE was positively correlated with the apoptotic rate of CD8+T cells.The difference of expression in Fas and FasL between active and inactive cases of SLE may induce the disability of immune tolerance.
Fas ligand
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CD28 interaction with B7 molecules, expressed on the membranes of antigen‐presenting cells, costimulates cytokine production, T‐cell proliferation and generation of cytotoxic lymphocytes. The expression of CD28 markers on CD4 + and CD8 + lymphocytes was studied in a group of subjects at various stages of HIV infection. A reduction in the percentage of CD28‐bearing CD4 + and CD8 + cell subsets was observed during the asymptomatic stage of the disease. This reduction was more pronounced in AIDS than in non‐AIDS patients. At the same time, an increase in the absolute CD8 + CD28 − cell number (greater in stage A than in stage B and C subjects) was observed in HIV‐infected patients. The finding of an altered pattern of CD28 expression on T cells might per se explain certain early defects in the cytokine pattern and in the immune response peculiar to HIV‐infected patients.
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Abstract According to CD28 molecule expression, CD8+ T cells can be classed as CD28bright, CD28dim, and CD28−. The CD28dim T cells were found to derive from mitogenic stimulated CD28− T cells but also from CD28bright T cells through a mechanism of CD28 down-modulation. Moreover, after prolonged in vitro interleukin-2 stimulation, clonal CD28bright cells showed a CD28dim expression before further evolution to a stable CD28− phenotype. This loss was concomitant with the disappearance of CD28 mRNA. A study of the cytokine production pattern revealed that CD28dim and CD28−T cell clones produced similar levels of type 1 and type 2 cytokines, which differed from those produced by the CD28bnght T cell clones. A high percentage of CD28dim and CD28− cells, with similarities in their cytokine production pattern, were found in the blood samples of HIV-infected patients, as compared to healthy donors. The CD28 down-modulation may account for the increased number of CD8+CD28− T cells in HIV-infected patients. J. Leukoc. Biol. 65: 641–648; 1999.
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SUMMARY To evaluate whether vertical HIV infection interferes with the expression of CD28 on T lymphocytes, 25 HIV-infected children and 29 seroreverted children born to HIV+ mothers were studied. The percentage of CD28− cells among CD8+ T lymphocytes was higher in HIV-infected children than in controls (P < 0.001). In fact, in HIV-infected children, this percentage was elevated from the first year of life, while in healthy seroreverted children, the proportion of CD28− cells among CD8+ cells rose progressively with age (r = 0.49; P = 0.008). In HIV+ children, the CD8+ CD28−, but not CD8+ CD28+ cell proportion was significantly correlated with immunological markers of disease progression, such as CD4+ cell loss (r = −0.65; P < 0.001) and the level of in vitro spontaneous lymphocyte apoptosis (r = 0.53; P = 0.03).
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