CD4 T-cell Apoptosis Research Articles

Rho Kinase Regulates Induction of T-Cell Immune Dysfunction in Abdominal Sepsis

T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho kinase inhibitor Y-27632 (5 mg/kg of body weight) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and percentage of regulatory T cells (CD4(+) CD25(+) Foxp3(+)) were determined by flow cytometry. Formation of gamma interferon (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of HMBG1, IL-17, and IL-6 were quantified by use of enzyme-linked immunosorbent assay (ELISA). It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T cells. Inhibition of Rho kinase activity decreased apoptosis and enhanced proliferation of CD4 T cells in septic animals. In addition, CLP-evoked induction of regulatory T cells in the spleen was abolished by Rho kinase inhibition. CLP reduced the levels of IFN-γ and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-γ but not IL-4 formation in the spleen. CLP increased plasma levels of high-mobility group box 1 (HMGB1) by 20-fold and IL-6 by 19-fold. Inhibition of Rho kinase decreased this CLP-evoked increase of HMGB1, IL-6, and IL-17 levels in the plasma by more than 60%, suggesting that Rho kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis.

Simvastatin Protects Against T Cell Immune Dysfunction in Abdominal Sepsis

Sepsis-triggered immune paralysis including T-cell dysfunction increases susceptibility to infections. Statins exert beneficial effects in patients with sepsis, although the mechanisms remain elusive. Herein, we hypothesized that simvastatin may attenuate T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (10 mg/kg) before cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and regulatory T cells (CD4CD25Foxp3) were quantified by use of flow cytometry. Formation of interferon γ (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of high-mobility box group 1 (HMBG1) and IL-6 were determined using enzyme-linked immunosorbent assay. Cecal ligation and puncture caused a clear-cut increase in apoptosis and decrease in proliferation in splenic CD4 T cells. It was found that simvastatin markedly reduced apoptosis and improved proliferation in CD4 T cells in septic mice. Moreover, CLP-induced formation of regulatory T cells in the spleen was abolished in simvastatin-treated animals. Cecal ligation and puncture greatly decreased the levels of IFN-γ and IL-4 in the spleen. Simvastatin completely reversed this sepsis-mediated inhibition of IFN-γ and IL-4 formation in the spleen. We observed that CLP increased plasma levels of HMBG1 by 25-fold and IL-6 by 99,595-fold. Notably, treatment with simvastatin abolished this CLP-evoked increase in HMBG1 and IL-6 levels in the plasma, suggesting that simvastatin is a potent inhibitor of systemic inflammation in sepsis. Lastly, it was found that simvastatin reduced CLP-induced bacteremia. In conclusion, these novel findings suggest that simvastatin is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, these protective effects of simvastatin on T-cell functions help to explain the protective effect of statins in patients with sepsis.

Mechanisms of HIV-associated lymphocyte apoptosis: 2010

The inevitable decline of CD4T cells in untreated infection with the Human immunodeficiency virus (HIV) is due in large part to apoptosis, one type of programmed cell death. There is accumulating evidence that the accelerated apoptosis of CD4T cells in HIV infection is multifactorial, with direct viral cytotoxicity, signaling events triggered by viral proteins and aberrant immune activation adding to normal immune defense mechanisms to contribute to this phenomenon. Current antiviral treatment strategies generally lead to reduced apoptosis, but this approach may come at the cost of preserving latent viral reservoirs. It is the purpose of this review to provide an update on the current understanding of the role and mechanisms of accelerated apoptosis of T cells in the immunopathogenesis of HIV infection, and to highlight potential ways in which this seemingly deleterious process could be harnessed to not just control, but treat HIV infection.

Characterization of ζ-associated protein, 70 kd (ZAP70)–deficient human lymphocytes

ζ-associated protein, 70 kd (ZAP70), deficiency in human subjects results in a combined immunodeficiency characterized by normal numbers of circulating CD4 T cells and CD8 lymphocytopenia. Patients who live beyond infancy can also experience autoimmune manifestations. We sought to further characterize the nature of the T-cell populations found in ZAP70-deficient patients and explored the mechanisms that might predispose them to autoimmunity. T-cell development was assessed by examining T-cell receptor (TCR) gene rearrangements and thymopoiesis by measuring TCR exclusion circle levels. TCR repertoire on CD4 and CD8 T-cell populations was assessed by means of flow cytometry. T-cell gene expression patterns were examined by means of exonic microarray analysis and apoptotic responses by means of Annexin V binding and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Cells displaying recombination events from all stages of TCR gene rearrangement were present in the peripheral blood of ZAP70-deficient patients; however, the late TCRD-deleting rearrangement was significantly reduced. TCR exclusion circle levels were also found to be low. Surprisingly, all Vβ families were detected in both CD4(+) and CD8(+) circulating T cells. Several Vβ families were significantly overrepresented, which is reminiscent of autoimmune disorders. Levels of mRNA for cytotoxic T lymphocyte-associated antigen 4, TGF-β, and IL-10 were found to be low, a signature of autoimmunity. Finally, Fas-mediated CD4 T-cell apoptosis was found to be reduced in vitro, and staining of thymus biopsy specimens revealed reduced thymocyte apoptosis. We show that in the absence of ZAP70, thymopoiesis is altered and differentiation to double-positive cells is hampered. Circulating T cells appear poorly regulated, do not differentiate into T(H)2 T cells, lack a number of inhibitory growth controls, and display reduced apoptosis, all predisposing patients to exaggerated inflammation and autoimmunity.

Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

Chronic HIV-1 infection can induce a significant decrease in CD127 expression on CD8 T cells, but the underlying mechanisms and immunological consequences are unclear. In this study, we investigated CD127 expression on CD8 T cells from a total of 51 HIV-1-infected subjects and 16 healthy individuals and analyzed the association between CD127 expression and CD8 T-cell apoptosis in these HIV-1-infected subjects. We found that CD127 expression on total CD8 T cells was significantly down-regulated, which was correlated with the increased CD8 T-cell apoptosis and disease progression of chronic HIV-1 infection. The in vitro addition of IL-7 efficiently rescued the spontaneous apoptosis of CD8 T cells from HIV-1-infected individuals. IL-7 stimulation also transiently down-regulated CD127 expression, whereas some of the CD127(-) CD8 T cells regained CD127 expression soon after IL-7 was retracted from the incubation medium. Thus, IL-7 stimulation reduced apoptosis of both CD127(+) and CD127(-)CD8 T cells to some degree. These data indicate that CD127 loss might impair IL-7 signaling and increase CD8 T-cell apoptosis during HIV-1 infection. This study, therefore, will extend the notion that IL-7 could be a good candidate for immunotherapy in HIV-1-infected patients.

RESUSCITATION WITH HYDROXYETHYL STARCH SOLUTION PREVENTS CD4+ T-LYMPHOCYTE APOPTOSIS AND MODULATES THE BALANCE OF T HELPER TYPE 1 AND T HELPER TYPE 2 RESPONSES IN THE RAT WITH TRAUMATIC VIRGULE/SHILL HEMORRHAGIC SHOCK

Trauma/hemorrhagic shock (TH/S) has been associated with inflammation and immunodisorders, leading to immunosuppression, multiorgan dysfunction, and death. However, little is known about the effect of resuscitation with different solutions on the immunological function. To address this issue, groups of male Sprague-Dawley rats were induced with TH/S by fracture in the left femur and continual bleeding to keep the MAP of 30 +/- 5 mmHg for 30 min, followed by resuscitation with 6% hydroxyethyl starch solution (HES), Ringer's lactate solution (RS), or 5% albumin (ALB), and the impact of resuscitation on the activation, differentiation, and survival of CD4 T cells was longitudinally examined after TH/S and resuscitation. After resuscitation, the MAP, as expected, gradually increased regardless of the type of fluids transfused. The percentage of CD4+ T cells decreased to 20% to 25%, and the ratio of T helper type 1 (TH1)/TH2 responses was significantly reduced in all TH/S rats, however, resuscitation with HES alone reversed the trends (49.4% +/- 9.7% vs. 55.2% +/- 2.6% in sham for CD4 T cells; 0.64 +/- 0.23 vs. 0.71 +/- 0.16 in sham for the ratio of TH1/TH2, P > 0.05 for both). Treatment with HES or ALB, but not RS, prevented CD4 T-cell apoptosis (sham, 7.23% +/- 3.4%; HES, 10.2% +/- 4.1%; RS, 15.2% +/- 5.4%; ALB, 10.6% +/- 4.3%; 48 h) and nuclear factor-kappaB p65 activation (sham, 0.17 +/- 0.04; HES, 0.34 +/- 0.05; RS, 0.41 +/- 0.09; ALB, 0.25 +/- 0.09; 48 h) induced by TH/S early after resuscitation. These data demonstrated that HES resuscitation modulated the balance of TH1 and TH2 responses and inhibited TH/S-related nuclear factor-kappaB activation and CD4 T-cell apoptosis in TH/S rats. Our findings provide new insights into understanding the TH/S-related immunodisorders and may aid in the design of new therapy for intervention of TH/S.

Comparison of chlordecone and estradiol effects on splenic T-cells in (NZB × NZW)F 1 mice

Previous studies have shown that treatment of ovariectomized females with 17-β estradiol (E2) accelerates the development of autoimmunity in the (NZB × NZW)F 1 murine lupus model. Treatment with estrogenic organochlorine pesticides (OCPs) such as chlordecone produces a similar effect. Although it is reasonable to postulate that the effects of chlordecone and related OCPs on autoimmunity are due to their estrogenic effects, this has not been clearly demonstrated. The objective of this study was to compare effects of chlordecone and E2 on splenic T lymphocyte parameters plausibly related to autoimmunity; specifically, on T-cell phenotype and functions. Ovariectomized (NZB × NZW)F 1 mice were treated for 6 weeks with implanted sustained-release pellets containing chlordecone or E2 at dosing rates shown previously to significantly shorten time to onset of disease. E2, but not chlordecone, increased the percentage of activated and memory CD4 T-cells, and reduced naive CD4 T-cells. E2 also elevated CD25 and glucocorticoid-induced TNF receptor (GITR) levels in CD4 T-cells, an effect not shared by chlordecone. On the other hand, both chlordecone and E2 increased Bcl-2 expression in CD4 T-cells and reduced CD4 T-cell apoptosis without affecting their proliferation. Although both treatments increased TNF-α and IL-2 secretion by CD4 T-cells, only chlordecone increased secretion of IFN-γ and GM-CSF. E2, but not chlordecone, increased IL-10 secretion. These observations indicate that although it is considered an estrogenic OCP, chlordecone exerts effects on splenic T-cells that are different in a number of ways from E2.

Recovery of CD4+ T Cells in HIV Patients With a Stable Virologic Response to Antiretroviral Therapy Is Associated With Polymorphisms of Interleukin-6 and Central Major Histocompatibility Complex Genes

We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors.

CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients

Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray's test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of < or =16, 16 to 24, and >24, respectively. Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

1391 POSTER Radiation-induced CD8 T-lymphocyte apoptosis predicts tumor sensitivity in head and neck cancer

Gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdCyd) is one of the anti-metabolites drugs that target DNA replication. We evaluated dFdCyd cytotoxicity and its radiosensitizing ability in human breast cancer cell lines, MCF-7 (wild-type p53) and MDA-MB-231 (mutant-type p53) along with normal mammary epithelial cell line (MCF-12) for comparison. Radiosensitivity and cytotoxicity were measured by the clonogenic survival assays. DNA DSBs was studied by Pulse Field Gel Electrophoresis (PFGE) and cell cycle distribution was analyzed by flow cytometry. MDA-MB-231 cells were the most sensitive to the cytotoxicity of dFdCyd (IC50 5 nM) then MCF-7 (IC50 10 nM), whereas MCF-12 cells were the most resistant to the cytotoxicity of dFdCyd (IC50 70 nM). MCF-12 and MCF-7 cell lines did not show any radiosensitization to dFdCyd, whereas the MDA-MB-231 cells showed significantly increased radioresistant to dFdCyd at equimolar concentration (p = 0.002) and at IC50 concentration (p < 0.001). The DNA double strand breaks (DSBs) repair showed that dFdCyd neither increases DNA DSBs nor decreases the rate of their repair in MCF-12 and MCF-7 cell lines, while the same treatment in MDA-MB-231 cell line led to decrease the rate of DSBs or increase the rate of DNA repair (p = 0.034). Therefore, dFdCyd is a cytotoxic agent, especially in the cancer cells irrespective of having wild-type or mutated p53 protein, but it is not effective as radiosensitizer in the cell lines used in this study. dFdCyd combined with radiation reduces the efficacy of chemo-radiotherapy in p53 mutated cells. Therefore, p53-mutated cancer could be a counter-indication for radiation–gemcitabine combined treatment.

Mechanisms of Apoptosis of T-Cells in Human Tuberculosis

The role of TGF-beta TNF-alpha FasL and Bcl-2 in apoptosis of CD4 T-cells during active TB was studied. Coculture of PBMC from TB patients with neutralizing antibodies to TGF-beta or TNF-alpha decreased spontaneous (P < or = 0.05) and MTB-induced (P < or = 0.02) T-cell apoptosis by 50-90%, but effects were not additive. Interestingly, only levels of TGF-beta in supernatants correlated with rates of spontaneous and MTB-induced apoptosis. FasL surface and mRNA expression were higher in unstimulated and MTB-stimulated PBMC from patients than controls, and neutralization of FasL abrogated apoptosis of T-cells from patients only. Intracellular Bcl-2 protein was lower among unstimulated CD4 T-cells from patients than those from controls (P < or = 0.02), and MTB stimulation reduced intracellular Bcl-2 content in CD4 T-cells from patients only (P < or = 0.001). These findings may indicate that, during TB, predisposition of CD4 T-cells to apoptosis may involve both low expression of Bcl-2, and excessive expression of TGF-beta TNF-alpha and FasL.

Do sensitive patients have sensitive tumors?

5516 Background: The concept of expecting radiosensitive tumors in patients genetically hypersensitive to radiation is not widely accepted. Here, we aim to assess whether the tumors of patients with increased lymphocyte apoptotic response with head and neck cancer have a better outcome than their normoresponsive counterparts. Methods: Seventy-five patients with head and neck cancer treated with curative radiation therapy (RT) were included in the KFS 00539–9-1997/SKL 00778–2-1999 prospective study aiming at assessing the value of CD8 T-lymphocyte apoptosis in predicting intrinsic radiosensitivity. Male to female ratio was 60/15, and median age was 59 years (35–85). Median radiation dose was 66 Gy (60–74.4) administered in median 41 days (37–58). Dose per fraction was 2 Gy in the majority of the patients (n = 70). Prior to RT, all patients were tested using a rapid (48 h) apoptosis assay where fresh blood samples were irradiated with 8-Gy X rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by gradual degradation of DNA (sub-G1 peak on the DNA histogram). Acute (CTC v2.0) and late (RTOG/EORTC) toxicities were graded in all patients. Median follow-up period was 31 months (23–43). Results: Following in vitro 8-Gy irradiation, median radiation-induced CD8 apoptosis was 20.88% (5.69–57.00%). Radiation-induced CD8 apoptosis significantly predicted grade 2 and 3 late effects. The area under the curve of the receiver-operated characteristic curve (sensitivity versus 1-specificity) of CD8 apoptosis was 0.83. Median time to locoregional relapse was 30 months (1–43 months). There were 13 locoregional relapses among the 37 patients showing CD8 apoptosis below the median compared to 5 of 38 who were above (p = 0.02). Two-year estimated locoregional relapse rate was 31% (95% CI: 17–45%) versus 14% (95% CI: 3–25%), respectively (p = 0.03). Conclusions: In patients with head and neck cancer treated with definitive or postoperative RT, in vivo apoptotic response of CD8 lymphocytes depends on genetic radiosensitivity, and the tumor follows the same genetic radiosensitivity of normal tissues. However, these findings should be confirmed prospectively, and future dose escalation studies could be stratified using the apoptosis assay. No significant financial relationships to disclose.

Radiation-induced late toxicity can be predicted by CD4 and CD8 T-lymphocyte apoptosis: results of a prospective study in 399 individual consenting patients

Radiation-induced late toxicity can be predicted by CD4 and CD8 T-lymphocyte apoptosis: results of a prospective study in 399 individual consenting patients

27 Prospective assessment of cd4 and cd8 T-lymphocyte apoptosis in the prediction of radiation-induced late toxicity in 399 individual consenting patients

27 Prospective assessment of cd4 and cd8 T-lymphocyte apoptosis in the prediction of radiation-induced late toxicity in 399 individual consenting patients

Increased HLA-DR Expression on Peripheral Blood Monocytes in Subsets of Subjects With Primary HIV Infection Is Associated With Elevated CD4 T-Cell Apoptosis and CD4 T-Cell Depletion

Increased HLA-DR Expression on Peripheral Blood Monocytes in Subsets of Subjects With Primary HIV Infection Is Associated With Elevated CD4 T-Cell Apoptosis and CD4 T-Cell Depletion

HIV/host interactions: new lessons from the Red Queen's country.

HIV/host interactions: new lessons from the Red Queen's country.

CD8 T-cell apoptosis induced by E. coli heat-labile enterotoxin B-subunit occurs via a novel pathway involving the NF-κB dependent activation of caspase-8 and caspase-3

CD8 T-cell apoptosis induced by E. coli heat-labile enterotoxin B-subunit occurs via a novel pathway involving the NF-κB dependent activation of caspase-8 and caspase-3

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway: Presented in part at the 12th World AIDS Conference, Geneva, Switzerland, 1998.

AbstractCD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

Quantitative Changes In T-Cell Populations After Left Ventricular Assist Device Implantation

Background—Left ventricular assist devices (LVADs) are currently being evaluated as permanent therapy for end-stage heart failure. Because life-threatening infections limit successful long-term device implantation, we investigated the relationship between quantitative T-cell defects in LVAD recipients and CD95-mediated T-cell apoptosis.Methods and Results—Immunological studies were performed in NYHA class IV patients awaiting cardiac transplantation who received either a TCI Heartmate left ventricular assist device (LVAD) or medical management. Fluorochrome-labeled Mabs were used in T-cell phenotypic analyses. T-cell apoptosis was measured by annexin V binding of T cells cultured in medium for 24 hours. Circulating serum levels of soluble CD95 were measured by ELISA. LVAD recipients had a relative lymphopenia and reduction in CD4 T-cell levels compared with NYHA class IV heart failure controls. These observations were confirmed in a longitudinal study in LVAD recipients, which showed that device implantation was accompanied by progressive and sustained reductions in circulating CD4 T-cell levels. These abnormalities in LVAD recipients were accompanied by increased levels of circulating soluble CD95 and by excessive CD4 and CD8 T-cell apoptosis. Susceptibility to induction of apoptosis was &gt;2-fold greater for CD4 T cells than for CD8 T cells.Conclusions—These results suggest that the reduction in CD4 T-cell levels accompanying LVAD implantation is a consequence of an augmented pathway of CD95-mediated apoptosis. The clinical consequences of these abnormalities may include increased prevalence of systemic infections.