T Lymphocyte-Mediated Cytolysis — A Comprehensive Theory II. Lytic vs. Nonlytic Interactions of T Lymphocytes

Measuring HIV p24 protein is a test which is more practical than determination of CD4+ T-lymphocyte counts and viral load, as it does not require a very sophisticated instrument and requires a lower cost. Independent predictive value of p24 to the decline of CD4+ T-lymphocytes, clinical progression and survival in HIV-infected patients have been reported. In this study, HIV-infected patients were found to have HIV p24 protein levels inversely proportional to CD4+ T-lymphocyte counts by using Spearman test (R2=0.225; p=0.0331). Studies on the correlation between HIV p24 protein levels and CD4+ T-lymphocyte counts in stage I HIV infection have not yet been reported. The aim of this study was to prove the correlation between HIV p24 protein levels and CD4+ T-lymphocytes in stage I HIV infection. Research issue was whether a correlation between HIV p24 protein levels and CD4+ T-lymphocyte counts in stage I HIVinfection existed ? The hypothesis was that a correlation between HIV p24 protein levels and CD4+ T-lymphocyte counts in stage I HIV infection existed. The study design was cross sectional observational. Subjects consisted of 30 stage I HIV-infected patients treated at the Infectious Disease Intermediate Care Unit, Dr. Soetomo Hospital and VCT Clinic of the Dr. Ramelan Naval Hospital, Surabaya from May to July 2014. Stage I HIV infection is an asymptomatic HIV infection or with persistent generalized lymphadenopathy and the patient is able to perform normal activities. Levels of p24 were measured by ELISA method and CD4+ T-lymphocyte counts using flowcytometry(BD FACSCaliburTM). The results were statistically analyzed using Pearson’s correlation test. HIV p24 protein levels in stage I of HIV infection ranged from 1.8 to 10.8 pg/mL, mean of 5.14 pg/mL and a standard deviation of 2.08 pg/mL. CD4+ T-lymphocyte counts decreased with a range of 49-559 cells /uL for absolute values and 4.42–26.02% for percentage values Correlations between blood p24 levels and CD4+ T-lymphocyte counts either absolute (r=–0.392, p=0.032) or percentage (r=–0.363, p=0.049) were found. In stage I HIV-infected patients, a negative correlation was found between p24 levels and CD4+ T-lymphocyte counts, in both CD4+T-lymphocyte counts as absolute and as well as percentage values. This negative correlation showed that the p24 HIV levels were inversely proportional to the CD4+ T-lymphocyte counts. HIV p24 protein levels have a possibility to be used predicting CD4+ T-lymphocyte counts

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Flow cytometric analysis of T lymphocytes and cytokines in aqueous humor of patients with varicella zoster virus-mediated acute retinal necrosis

BMC Ophthalmology ◽

10.1186/s12886-021-01951-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hao Kang ◽

Yunbo Wei ◽

Ming Liu ◽

Di Yu ◽

Yong Tao

Keyword(s):

T Lymphocytes ◽

Varicella Zoster Virus ◽

Aqueous Humor ◽

T Lymphocyte ◽

Lymphocyte Subsets ◽

Flow Cytometric Analysis ◽

T Lymphocyte Subsets ◽

Varicella Zoster ◽

Flow Cytometric ◽

Cd8 T Lymphocytes

Abstract Background The purpose of this study is to investigate the aqueous humor (AH) T lymphocyte subsets and cytokines of acute retinal necrosis (ARN) to elucidate the immunologic inflammatory features of this disorder. Methods Three patients with ARN infected with varicella zoster virus (VZV) who underwent multiple intravitreal injections of ganciclovir were enrolled in this study. The control group consisted of four non-infectious patients with acute anterior uveitis (AAU). Flow cytometric analysis was performed on the lymphocyte subsets from the AH and peripheral blood (PB) samples during the active phase of intraocular inflammation. Five inflammatory cytokines were measured in each AH sample and various clinical characteristics were also assessed. Results VZV deoxyribonucleic acid (DNA) was detected by real-time polymerase chain reaction (PCR) in AH from all the ARN patients, who showed higher CD8+ T lymphocytes population in AH than the AAU patients (p = 0.006). CD4/CD8 ratios of T lymphocytes and the percentage of CD8 + CD25+ T lymphocytes in AH were significantly lower in ARN than in AAU (p = 0.006; p = 0.012). In the ARN patients, the percentages of CD4+ and CD8+ T lymphocytes in AH were higher than those found in PB. The percentage of CD4 + CD25+ T lymphocytes in AH was significantly higher than the proportion in PB in the AAU patients (p = 0.001). Immunoregulatory cytokine Interleukin-10 in AH was significantly elevated in the ARN patients in comparison with the case of the AAU patients (p = 0.036). In ARN, the copy number of VZV DNA in AH positively correlated with the percentage of CD8+ T lymphocytes in AH and negatively correlated with the CD4/CD8 ratio in AH during the course of disease treatment (p = 0.009, r = 0.92; p = 0.039, r = − 0.834). Conclusion The ARN patients caused by VZV had different intraocular T lymphocyte subsets and cytokines profile than those of the non-infectious patients. High percentages of CD8+ T lymphocytes and low CD4/CD8 T cell ratios may be a potential biomarker for diagnosis of viral-infectious uveitis. T lymphocytes examination at the inflammatory sites has the potential to become a useful research tool for differentiating viral and non-viral uveitis.

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Regulatory T lymphocyte infiltration in metastatic breast cancer—an independent prognostic factor that changes with tumor progression

Breast Cancer Research ◽

10.1186/s13058-021-01403-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Jenny Stenström ◽

Ingrid Hedenfalk ◽

Catharina Hagerling

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Lymph Node ◽

Prognostic Factor ◽

T Lymphocytes ◽

T Lymphocyte ◽

Metastatic Breast ◽

Distant Metastases ◽

Independent Prognostic Factor ◽

Primary Tumors

Abstract Background Patients diagnosed with metastatic breast cancer have poor outcome with a median survival of approximately 2 years. While novel therapeutic options are urgently needed, the great majority of breast cancer research has focused on the primary tumor and less is known about metastatic breast cancer and the prognostic impact of the metastatic tumor microenvironment. Here we investigate the immune landscape in unique clinical material. We explore how the immune landscape changes with metastatic progression and elucidate the prognostic role of immune cells infiltrating primary tumors and corresponding lymph node and more importantly distant metastases. Methods Immunohistochemical staining was performed on human breast cancer tissue microarrays from primary tumors (n = 231), lymph node metastases (n = 129), and distant metastases (n = 43). Infiltration levels of T lymphocytes (CD3+), regulatory T lymphocytes (Tregs, FOXP3+), macrophages (CD68+), and neutrophils (NE+) were assessed in primary tumors. T lymphocytes and Tregs were further investigated in lymph node and distant metastases. Results T lymphocyte and Treg infiltration were the most clinically important immune cell populations in primary tumors. Infiltration of T lymphocytes and Tregs in primary tumors correlated with proliferation (P = 0.007, P = 0.000) and estrogen receptor negativity (P = 0.046, P = 0.026). While both T lymphocyte and Treg infiltration had a negative correlation to luminal A subtype (P = 0.031, P = 0.000), only Treg infiltration correlated to luminal B (P = 0.034) and triple-negative subtype (P = 0.019). In primary tumors, infiltration of T lymphocytes was an independent prognostic factor for recurrence-free survival (HR = 1.77, CI = 1.01–3.13, P = 0.048), while Treg infiltration was an independent prognostic factor for breast cancer-specific survival (HR = 1.72, CI = 1.14–2.59, P = 0.01). Moreover, breast cancer patients with Treg infiltration in their distant metastases had poor post-recurrence survival (P = 0.039). Treg infiltration levels changed with metastatic tumor progression in 50% of the patients, but there was no significant trend toward neither lower nor higher infiltration. Conclusion Treg infiltration could have clinical applicability as a prognostic biomarker, deciphering metastatic breast cancer patients with worse prognosis, and accordingly, could be a suitable immunotherapeutic target for patients with metastatic breast cancer. Importantly, half of the patients had changes in Treg infiltration during the course of metastatic progression emphasizing the need to characterize the metastatic immune landscape.

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O10: METFORMIN TREATMENT IMPROVES LYMPHOCYTE METABOLISM IN A MOUSE MODEL OF MAJOR SURGERY

British Journal of Surgery ◽

10.1093/bjs/znab117.010 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

TF Jones ◽

A Gutierrez ◽

del Arroyo ◽

SM Henson ◽

GL Ackland

Keyword(s):

T Lymphocytes ◽

Mouse Model ◽

T Lymphocyte ◽

Major Surgery ◽

P Value ◽

Free Access ◽

Mitochondrial Bioenergetics ◽

Metformin Treatment ◽

Respiratory Capacity

Abstract Introduction Lymphopaenia is common after major surgery and associated with poor outcome. T-lymphocytes restrain damaging innate inflammation. Major surgery impairs T-lymphocyte metabolism in humans, which promotes lymphopaenia. Metformin is known to improve mitochondrial bioenergetics in models of inflammation. Firstly, we hypothesised that a mouse model of major surgery would demonstrate impaired T-lymphocyte metabolism and secondly, that metformin treatment in vivo would reverse the phenotype. Method Male C57Bl/6 mice aged between 8 and 12 weeks were housed in a specific pathogen free environment with free access to food and water. Animals were dosed with either vehicle (phosphate buffered saline, 20 ml/kg) or metformin (250 mg/kg) daily via intraperitoneal injection for four days prior to and after surgery. A partial hepatectomy was performed under isofluorane anaesthesia. Naive littermates were used as controls. All experiments were performed according to the Animals (Scientific Procedures) Act 1986. Splenic T-lymphocytes were isolated by negative selection using magnetic beads. Mitochondrial bioenergetics were measured using a Seahorse Extracellular Flux analyser. Parametric statistical analysis was performed and a p-value < 0.05 was chosen to represent significance. Result T-lymphocytes demonstrated reduced spare respiratory capacity (SRC, 285 vs 497 %, p=0.004) after surgery compared to naive controls. Metformin treatment in vivo reversed this observation and SRC was comparable to naive (437 vs 497 %, p=0.34). Metformin treatment in vitro increased spare respiratory capacity in T-lymphocytes from mice after surgery compared to naive (change from untreated, 187 vs 91 %, p=0.03). Conclusion Perioperative metformin treatment improved T-lymphocyte metabolism in a mouse model of major surgery. Take-home message Metformin is a potential treatment for the lymphocyte metabolic dysfunction observed after surgery.

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T lymphocyte-dependent B lymphocyte proliferative response to antigen. I Genetic restriction of the stimulation of B lymphocyte proliferation.

Journal of Experimental Medicine ◽

10.1084/jem.153.4.871 ◽

1981 ◽

Vol 153 (4) ◽

pp. 871-882 ◽

Cited By ~ 20

Author(s):

H Y Tse ◽

J J Mond ◽

W E Paul

Keyword(s):

T Lymphocytes ◽

B Lymphocytes ◽

T Lymphocyte ◽

Lymphocyte Proliferation ◽

B Lymphocyte ◽

Antigen Specificity ◽

Apparent Lack ◽

The Face ◽

Stimulation Of

For the purpose of examining more closely the interaction between T and B lymphocytes, we have developed an in vitro T lymphocyte-dependent B lymphocyte proliferation assay. Proliferation of B lymphocytes in response to antigen was found to depend on the presence of primed T lymphocytes; the B lymphocytes could be derived from nonprimed animals. It appears that these B cells were nonspecifically recruited to proliferate. This nonspecific recruitment, however, was found to be Ir-gene restricted in that B lymphocytes from B10.S mice, which are genetic nonresponders to the polymer Glu60-Ala30-Tyr10 (GAT), could not be stimulated by GAT-primed (responder X nonresponder) F1 T cells. The apparent lack of antigen specificity in the face of Ir gene-restricted T-B interaction may have important implications in our understanding of the recognition unit(s) on T lymphocytes.

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CD4+ T Lymphocytes from Calves Immunized withAnaplasma marginale Major Surface Protein 1 (MSP1), a Heteromeric Complex of MSP1a and MSP1b, Preferentially Recognize the MSP1a Carboxyl Terminus That Is Conserved among Strains

Infection and Immunity ◽

10.1128/iai.69.11.6853-6862.2001 ◽

2001 ◽

Vol 69 (11) ◽

pp. 6853-6862 ◽

Cited By ~ 50

Author(s):

Wendy C. Brown ◽

Guy H. Palmer ◽

Harris A. Lewin ◽

Travis C. McGuire

Keyword(s):

T Lymphocytes ◽

T Lymphocyte ◽

Protective Immunity ◽

B Lymphocyte ◽

Surface Protein ◽

Specific Response ◽

Major Surface Protein ◽

Ifn Γ ◽

Major Surface ◽

Lymphocyte Responses

ABSTRACT Native major surface protein 1 (MSP1) of the ehrlichial pathogenAnaplasma marginale induces protective immunity in calves challenged with homologous and heterologous strains. MSP1 is a heteromeric complex of a single MSP1a protein covalently associated with MSP1b polypeptides, of which at least two (designated MSP1F1 and MSP1F3) in the Florida strain are expressed. Immunization with recombinant MSP1a and MSP1b alone or in combination fails to provide protection. The protective immunity in calves immunized with native MSP1 is associated with the development of opsonizing and neutralizing antibodies, but CD4+ T-lymphocyte responses have not been evaluated. CD4+ T lymphocytes participate in protective immunity to ehrlichial pathogens through production of gamma interferon (IFN-γ), which promotes switching to high-affinity immunoglobulin G (IgG) and activation of phagocytic cells to produce nitric oxide. Thus, an effective vaccine for A. marginaleand related organisms should contain both T- and B-lymphocyte epitopes that induce a strong memory response that can be recalled upon challenge with homologous and heterologous strains. This study was designed to determine the relative contributions of MSP1a and MSP1b proteins, which contain both variant and conserved amino acid sequences, in stimulating memory CD4+ T-lymphocyte responses in calves immunized with native MSP1. Peripheral blood mononuclear cells and CD4+ T-cell lines from MSP1-immunized calves proliferated vigorously in response to the immunizing strain (Florida) and heterologous strains of A. marginale. The conserved MSP1-specific response was preferentially directed to the carboxyl-terminal region of MSP1a, which stimulated high levels of IFN-γ production by CD4+ T cells. In contrast, there was either weak or no recognition of MSP1b proteins. Paradoxically, all calves developed high titers of IgG antibodies to both MSP1a and MSP1b polypeptides. These findings suggest that in calves immunized with MSP1 heteromeric complex, MSP1a-specific T lymphocytes may provide help to MSP1b-specific B lymphocytes. The data provide a basis for determining whether selected MSP1a CD4+ T-lymphocyte epitopes and selected MSP1a and MSP1b B-lymphocyte epitopes presented on the same molecule can stimulate a protective immune response.

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Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

Gut ◽

10.1136/gut.45.3.382 ◽

1999 ◽

Vol 45 (3) ◽

pp. 382-388 ◽

Cited By ~ 84

Author(s):

S D Hearing ◽

M Norman ◽

C S J Probert ◽

N Haslam ◽

C M Dayan

Keyword(s):

Ulcerative Colitis ◽

T Lymphocytes ◽

Disease Severity ◽

T Lymphocyte ◽

Peripheral Blood ◽

Steroid Treatment ◽

Steroid Resistance ◽

Severe Ulcerative Colitis ◽

Steroid Sensitivity

BACKGROUNDUp to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown.AIMTo investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes.METHODSEighteen patients with severe UC were studied. After seven days’ treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured.RESULTSIn vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups.CONCLUSIONSResults suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

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Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.01715-08 ◽

2008 ◽

Vol 83 (2) ◽

pp. 572-583 ◽

Cited By ~ 49

Author(s):

Mareike Meythaler ◽

Amanda Martinot ◽

Zichun Wang ◽

Sarah Pryputniewicz ◽

Melissa Kasheta ◽

...

Keyword(s):

Immune Response ◽

T Lymphocytes ◽

T Lymphocyte ◽

Immune Activation ◽

Rhesus Macaques ◽

Lymphocyte Apoptosis ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

Siv Infection ◽

Species Specific

ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.

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Increased Frequency of Regulatory T Cells and T Lymphocyte Activation in Persons with Previously Treated Extrapulmonary Tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.05263-11 ◽

2011 ◽

Vol 19 (1) ◽

pp. 45-52 ◽

Cited By ~ 29

Author(s):

Alexandre S. de Almeida ◽

Christina T. Fiske ◽

Timothy R. Sterling ◽

Spyros A. Kalams

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Pulmonary Tuberculosis ◽

Treg Cell ◽

T Lymphocyte ◽

Extrapulmonary Tuberculosis ◽

Lymphocyte Activation ◽

Content Type ◽

T Lymphocyte Activation ◽

Previously Treated

ABSTRACTExtrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4+T lymphocytes in general, are important in the host immune response toMycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions beforeM. tuberculosisinfection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts withM. tuberculosisinfection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4+CD25hiCD127lowFoxP3+cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls withM. tuberculosisinfection, and 18 controls withoutM. tuberculosisinfection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.20%) (P= 0.001). The median proportion of CD4+T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4+T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.32%) (P= 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4+T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.

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