Costimulatory Pathways Mediate Monocyte-Dependent Lymphocyte Apoptosis in HIV

Lewis, Dorothy E.; Tang, Derek S. Ng; Wang, Xiaoping; Kozinetz, Claudia A.

doi:10.1006/clim.1998.4663

Cited by 22 publications

(16 citation statements)

References 42 publications

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“…Thus, it is possible that down-regulation of CD28 by CD80 could be a mechanism for dampening the immune response. Consistent with this suggestion is the observation that CD8 ϩ CD28 dim T cells in HIV are highly susceptible to apoptosis (26,59). In this case, development of CD8 ϩ CD28 null T cells could be a way to escape death-inducing signals after TCR triggering.…”

Section: Discussionmentioning

confidence: 65%

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Lewis

Merched-Sauvage

Goronzy

et al. 2004

Journal of Biological Chemistry

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Replicative senescence of human T cells is characterized by the loss of CD28 expression, exemplified by the clonal expansion of CD28null T cells during repeated stimulation in vitro as well as in chronic inflammatory and infectious diseases and in the normal course of aging. Because CD28 is the major costimulatory receptor for the induction of T cell-mediated immunity, the mechanism(s) underlying CD28 loss is of paramount interest. Current models of replicative senescence involve protracted procedures to generate CD28 null cells from CD28 ؉ precursors; hence, a T-cell line model was used to examine the dynamics of CD28 expression. Here, we show the versatility of the JT and Jtag cell lines in tracking CD28 null 7 CD28 hi phenotypic transitions. JT and Jtag cells were CD28 null and CD28 lo , respectively, but expressed high levels of CD28 when exposed to phorbol 12-myristate 13-acetate. This was a result of the reconstitution of the CD28 gene transcriptional initiator (INR). Tumor necrosis factor-␣ reduced CD28 expression because of the inhibition of INR-driven transcription. Ligation of CD28 by an antibody or by CD80 also down-regulated CD28 transcription through the same mechanism, providing evidence that CD28 can generate a T cell receptor-independent signal with a unique biological outcome. Collectively, these data unequivocally demonstrate the critical role of the INR in the regulation of CD28 expression. T cell lines with transient expression of CD28 are invaluable in the dissection of the biochemical processes involved in the transactivation of the CD28 INR, the silencing of which is a key event in the ontogenesis of senescent T cells.

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Section: Discussionmentioning

confidence: 65%

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Lewis

Merched-Sauvage

Goronzy

et al. 2004

Journal of Biological Chemistry

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“…In this regard, CD28 has been shown to be critical in events that lead to migration of T cells to B cell areas (40). Finally, costimulatory pathways may offer potential therapeutic avenues, especially considering numerous other studies that have shown similar APC deficiencies with monocytes and dendritic cells of HIV-infected patients (23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of CD80 and CD86 expression on Ag-presenting monocytes and dendritic cells has been described in HIV infection, with predicted deleterious consequences on Ag-responsive immune competent cells including T cell apoptosis (23), induction of premature B cell terminal differentiation (24), and loss of T cell responsiveness to antigenic stimulation (25)(26)(27). Furthermore, abnormal expression of CD80 and CD86 on T cells of HIV-infected patients has been described and thought to be associated with the Department of Health and Human Services, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 effects of HIV-induced immune activation (28), similar to what occurs in other inflammatory diseases (29,30).…”

Section: H Uman Immunodeficiency Virus Infection Leads To Profound Immentioning

confidence: 99%

Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function

Malaspina

Moir

Kottilil

et al. 2003

The Journal of Immunology

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HIV infection leads to numerous immunologic defects, including impaired B cell function. An effective humoral response requires bidirectional interactions between B cells and CD4+ T cells, critical of which are interactions between CD80/CD86 expressed on activated B cells and CD28 expressed on responder CD4+ T cells. In the present study, we examined the effect of active HIV replication on B cell costimulatory function. Induction of CD80/CD86 on B cells following B cell receptor and CD40 triggering and responsiveness of CD4+ T cells to activated B cells were investigated in a system where B cells of HIV-infected patients were compared concurrently to B cells of HIV-negative donors. In contrast to HIV-aviremic patients, B cells of HIV-viremic patients were ineffective at stimulating CD4+ T cells, as measured by the induction of activation markers and proliferation. The importance of interactions of CD80/CD86 and CD28 in activating CD4+ T cells was clear; the ablation of a normal response following the addition of neutralizing anti-CD86/CD80 Abs mirrored the response of CD4+ T cells to B cells of HIV-viremic patients, while the addition of exogenous CD28 ligands partially restored the poor CD4+ T cell response to the B cells of HIV-viremic patients. Ineffective B cell costimulatory function in HIV-viremic patients was associated with low induction of CD80/CD86 expression on B cells. Our findings further delineate the scope of defects associated with cognate B cell-CD4+ T cell interactions in HIV infection and suggest that therapeutic interventions designed to enhance CD28-dependent costimulatory pathways may help restore immune functions.

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“…Results of the analysis of T-cell apoptosis in freshly isolated blood samples from HIV-infected persons most likely reflect the rate of cell death in vivo, thus providing valuable insight into the pathogenesis of this disease. Previous reports of immediate ex vivo apoptosis in HIV-infected adults (12,13,16) and children (6), including a recent study which utilized the annexin V assay (16), indicated low levels of cell death. In contrast, a study utilizing the dye Apostain, which is reported to detect early apoptotic cells, found that over half of freshly isolated lymphocytes underwent apoptosis in HIV-infected adults (1).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis in T-Lymphocyte Subsets in Human Immunodeficiency Virus-Infected Children Measured Immediately Ex Vivo and following In Vitro Activation

Niehues

McCloskey

Ndagijimana

et al. 2001

Clin Diagn Lab Immunol

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Phosphatidylserine molecules are translocated to the outer plasma membrane of lymphocytes undergoing apoptosis and can be detected by the binding of fluorochrome-conjugated annexin V. Using the annexin V assay, we examined CD4 and CD8 T cells from human immunodeficiency virus (HIV)-infected children for apoptosis upon isolation or following in vitro culture. Immediate ex vivo analysis or overnight culture showed significantly higher levels of apoptosis in CD8 cells than in CD4 cells. Following culture with the activating stimulus phytohemagglutinin or anti-CD3 monoclonal antibody, we observed an increase in the percentage of apoptotic CD4 cells, whereas there was no change in the rate of CD8 cell death. These results demonstrate that in HIV-infected children, CD8 apoptosis may occur at a greater rate than CD4 apoptosis in vivo; greater CD4 depletion may be observed due to more efficient mechanisms for peripheral lymphocyte replacement in the CD8 compartment. Furthermore, our data suggest that CD8 lymphocytes may be maximally activated in vivo, a condition which may lead to the exhaustion of CD8-mediated immunity. These findings clarify the differences between the CD4 and CD8 apoptotic responses to HIV.

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Costimulatory Pathways Mediate Monocyte-Dependent Lymphocyte Apoptosis in HIV

Cited by 22 publications

References 42 publications

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function

Apoptosis in T-Lymphocyte Subsets in Human Immunodeficiency Virus-Infected Children Measured Immediately Ex Vivo and following In Vitro Activation

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