T-Cell Responses to Mitogens in Atomic Bomb Survivors: A Decreased Capacity to Produce Interleukin 2 Characterizes the T Cells of Heavily Irradiated Individuals

2001 ◽  
Vol 155 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Yoichiro Kusunoki ◽  
Tomonori Hayashi ◽  
Yukari Morishita ◽  
Mika Yamaoka ◽  
Mayumi Maki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Atomic Bomb ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Atomic Bomb Survivors ◽  
Cell Responses

scholarly journals Reduced Protection from Simian Immunodeficiency Virus SIVmac251 Infection Afforded by Memory CD8+ T Cells Induced by Vaccination during CD4+ T-Cell Deficiency

2008 ◽  
Vol 82 (19) ◽  
pp. 9629-9638 ◽  
Author(s):  
Monica Vaccari ◽  
Joseph Mattapallil ◽  
Kaimei Song ◽  
Wen-Po Tsai ◽  
Anna Hryniewicz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection.

scholarly journals Helicobacterpylori-Specific CD4+ CD25high Regulatory T Cells Suppress Memory T-Cell Responses to H. pylori in Infected Individuals

2003 ◽  
Vol 71 (4) ◽  
pp. 1755-1762 ◽  
Author(s):  
Anna Lundgren ◽  
Elisabeth Suri-Payer ◽  
Karin Enarsson ◽  
Ann-Mari Svennerholm ◽  
B. Samuel Lundin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Duodenal Mucosa ◽  
Peptic Ulcers ◽  
Memory Cells ◽  
Cell Responses ◽  
H Pylori

ABSTRACT Helicobacter pylori colonizes the gastric and duodenal mucosa. The infection normally persists for life and causes peptic ulcers and gastric cancer in a subset of infected individuals. We hypothesized that the inability to clear the infection may be a consequence of H. pylori-specific regulatory T cells that actively suppress T-cell responses. Therefore, we characterized the T-cell responses to H. pylori in H. pylori-infected individuals without any subjective symptoms and in uninfected control subjects and investigated the role of regulatory CD4+ CD25high T cells during infection. The stimulation of CD4+ peripheral blood T cells with monocyte-derived dendritic cells pulsed with a membrane preparation of H. pylori resulted in proliferation and gamma interferon production in both infected and uninfected individuals. Sorted memory cells from infected individuals responded less than cells from uninfected subjects, and the unresponsiveness could be abolished by depletion of CD4+ CD25high regulatory T cells or the addition of interleukin 2. Furthermore, CD4+ CD25high T cells suppressed H. pylori-induced responses in cocultures with CD25low/− cells. Tetanus toxoid induced comparable responses in memory cells from infected and uninfected individuals in both the presence and the absence of regulatory T cells, suggesting that the suppression was H. pylori specific. In conclusion, we have shown that H. pylori-infected individuals have impaired memory CD4+ T-cell responses to H. pylori that are linked to the presence of H. pylori-specific regulatory T cells that actively suppress the responses.

scholarly journals CD46 Engagement on Human CD4+ T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

2010 ◽  
Vol 78 (12) ◽  
pp. 5295-5306 ◽  
Author(s):  
Steven M. Truscott ◽  
Getahun Abate ◽  
Jeffrey D. Price ◽  
Claudia Kemper ◽  
John P. Atkinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Development ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Immune Defense ◽  
Cell Functions ◽  
Cell Responses ◽  
Regulatory Type

ABSTRACT Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4+ T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4+ T cells activated in vitro with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4+ T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4+ T cells suppress mycobacterium-specific CD4+, CD8+, and γ9δ2 TCR+ T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of γ9δ2 TCR+ T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.

scholarly journals Comparisons of CD8+ T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness

2009 ◽  
Vol 83 (6) ◽  
pp. 2728-2742 ◽  
Author(s):  
Prasanna Jagannathan ◽  
Christine M. Osborne ◽  
Cassandra Royce ◽  
Maura M. Manion ◽  
John C. Tilton ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Hiv Infection ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8+ T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8+ T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8+ T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8+ T cells were predominantly CD27+45RO+ for HIV and CD27−45RA+ for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8+ T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8+ T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8+ T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.

scholarly journals Diminished Proliferation of Human Immunodeficiency Virus-Specific CD4+ T Cells Is Associated with Diminished Interleukin-2 (IL-2) Production and Is Recovered by Exogenous IL-2

2003 ◽  
Vol 77 (20) ◽  
pp. 10900-10909 ◽  
Author(s):  
Christiana Iyasere ◽  
John C. Tilton ◽  
Alison J. Johnson ◽  
Souheil Younes ◽  
Bader Yassine-Diab ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Chronic Phase ◽  
T Cell Responses ◽  
In Vitro Proliferation ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Virus-specific CD4+ T-cell function is thought to play a central role in induction and maintenance of effective CD8+ T-cell responses in experimental animals or humans. However, the reasons that diminished proliferation of human immunodeficiency virus (HIV)-specific CD4+ T cells is observed in the majority of infected patients and the role of these diminished responses in the loss of control of replication during the chronic phase of HIV infection remain incompletely understood. In a cohort of 15 patients that were selected for particularly strong HIV-specific CD4+ T-cell responses, the effects of viremia on these responses were explored. Restriction of HIV replication was not observed during one to eight interruptions of antiretroviral therapy in the majority of patients (12 of 15). In each case, proliferative responses to HIV antigens were rapidly inhibited during viremia. The frequencies of cells that produce IFN-γ in response to Gag, Pol, and Nef peptide pools were maintained during an interruption of therapy. In a subset of patients with elevated frequencies of interleukin-2 (IL-2)-producing cells, IL-2 production in response to HIV antigens was diminished during viremia. Addition of exogenous IL-2 was sufficient to rescue in vitro proliferation of DR0101 class II Gag or Pol tetramer+ or total-Gag-specific CD4+ T cells. These observations suggest that, during viremia, diminished in vitro proliferation of HIV-specific CD4+ T cells is likely related to diminished IL-2 production. These results also suggest that relatively high frequencies of HIV-specific CD4+ T cells persist in the peripheral blood during viremia, are not replicatively senescent, and proliferate when IL-2 is provided exogenously.

scholarly journals Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3978-3989 ◽  
Author(s):  
April L. Ferre ◽  
Peter W. Hunt ◽  
J. William Critchfield ◽  
Delandy H. Young ◽  
Megan M. Morris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Surveillance ◽  
Interleukin 2 ◽  
Rectal Mucosa ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Elite Controllers ◽  
Cell Responses ◽  
Hiv 1

AbstractThere exists a unique group of persons who are able to durably control HIV in the absence of therapy. The mechanisms of control in these persons remain poorly defined. In this study, we examined CD8+ T-cell responses in blood and rectal mucosa from 17 “elite controllers” (viral load < 75 copies/mL), 11 “viremic controllers” (75-2000 copies/mL), 14 noncontrollers (> 10 000 copies/mL), and 10 antiretroviral-treated persons (< 75 copies/mL). Production of interferon-γ, interleukin-2, tumor necrosis factor-α, macrophage inflammatory protein-1β, and CD107a by CD8+ T cells in response to HIV-1 Gag stimulation was measured using flow cytometry. Our hypothesis was that “polyfunctional” T cells producing multiple antiviral factors would be most abundant in mucosal tissues of HIV controllers. Mucosal CD8+ T-cell responses were significantly stronger and more complex in controllers than in antiretroviral-suppressed persons (P = .0004). The frequency of 4-function responses in rectal mucosa was higher in controllers than in noncontrollers and patients on therapy (P < .0001). Mucosal responses in controllers were frequently stronger and more complex than blood responses. These findings demonstrate that many controllers mount strong, complex HIV-specific T-cell responses in rectal mucosa. These responses may play an important role in mucosal immune surveillance, as suggested by their relative enrichment among persons who control HIV in the absence of therapy.

scholarly journals Monofunctional and Polyfunctional CD8+ T Cell Responses to Human Herpesvirus 8 Lytic and Latency Proteins

2010 ◽  
Vol 17 (10) ◽  
pp. 1507-1516 ◽  
Author(s):  
Lauren Lepone ◽  
Giovanna Rappocciolo ◽  
Emilee Knowlton ◽  
Mariel Jais ◽  
Paolo Piazza ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Primary Effusion Lymphoma ◽  
Interleukin 2 ◽  
Human Herpesvirus ◽  
T Cell Responses ◽  
Human Herpesvirus 8 ◽  
Nuclear Antigen ◽  
Herpesvirus 8 ◽  
Cell Responses

ABSTRACT Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. It is postulated that CD8+ T cell responses play an important role in controlling HHV-8 infection and preventing development of disease. In this study, we investigated monofunctional and polyfunctional CD8+ T cell responses to HHV-8 lytic proteins gB (glycoprotein B) and K8.1 and latency proteins LANA-1 (latency-associated nuclear antigen-1) and K12. On the basis of our previous findings that dendritic cells (DC) reveal major histocompatibility complex (MHC) class I epitopes in gB, we used a DC-based system to identify 2 novel epitopes in gB, 2 in K8.1, 5 in LANA-1, and 1 in K12. These new HHV-8 epitopes activated monofunctional and polyfunctional CD8+ T cells that produced various combinations of gamma interferon, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1β, and cytotoxic degranulation marker CD107a in healthy HHV-8-seropositive individuals. We were also able to detect HHV-8-specific CD8+ T cells in peripheral blood samples using HLA A*0201 pentamer complexes for one gB epitope, one K8.1 epitope, two LANA-1 epitopes, and one K12 epitope. These immunogenic regions of viral lytic and latency proteins could be important in T cell control of HHV-8 infection.

scholarly journals Rap1 Functions as a Key Regulator of T-Cell and Antigen-Presenting Cell Interactions and Modulates T-Cell Responses

2002 ◽  
Vol 22 (4) ◽  
pp. 1001-1015 ◽  
Author(s):  
Koko Katagiri ◽  
Masakazu Hattori ◽  
Nagahiro Minato ◽  
Tatsuo Kinashi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses ◽  
Adhesive Interactions ◽  
Antigen Presenting ◽  
Rap1 Activation

ABSTRACT Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecules (ICAMs) are important. However, it is not well understood what signaling molecules regulate this process and how the modulation of adhesive events influences T-cell activation. Here we show that Rap1 is activated in T cells in an antigen-dependent manner and accumulated at the contact site of T-cell and antigen-loaded APC. Inhibition of Rap1 activation by a dominant-negative Rap1 or SPA-1, a Rap1 GTPase-activating protein, abrogates LFA-1-ICAM-1-mediated adhesive interactions with antigen-pulsed APC and the subsequent T-cell-receptor triggering and interleukin-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild-type Rap1 enhances these responses but culminates in apoptosis by Fas and FasL. Thus, Rap1 functions as a key regulator of T-cell and APC interactions and modulates T-cell responses from productive activation to activation-induced cell death by regulating the strength of adhesive interactions. Moreover, constitutive Rap1 activation rendered T cells unresponsive with accumulation of p27Kip1. Our study indicates that the activation state of Rap1 has a decisive effect on the T-cell response to antigen.

scholarly journals Changes in Paracrine Interleukin-2 Requirement, CCR7 Expression, Frequency, and Cytokine Secretion of Human Immunodeficiency Virus-Specific CD4+ T Cells Are a Consequence of Antigen Load

2006 ◽  
Vol 81 (6) ◽  
pp. 2713-2725 ◽  
Author(s):  
John C. Tilton ◽  
Marlise R. Luskin ◽  
Alison J. Johnson ◽  
Maura Manion ◽  
Claire W. Hallahan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cytokine Production ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
H3n2 Virus ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Virus-specific CD4+ T-cell responses are thought to be required for the induction and maintenance of many effective CD8+ T-cell and B-cell immune responses in experimental animals and humans. Although the presence of human immunodeficiency virus (HIV)-specific CD4+ T cells has been documented in patients at all stages of HIV infection, many fundamental questions regarding their frequency and function remain. A 10-color, 12-parameter flow cytometric panel was utilized to examine the frequency, memory phenotype (CD27, CCR7, and CD45RA), and cytokine production (interleukin-2 [IL-2], gamma interferon, and tumor necrosis factor alpha) of CD4+ T cells specific for HIV antigens as well as for adenovirus, Epstein-Barr virus (EBV), influenza H1N1 virus, influenza H3N2 virus, cytomegalovirus, varicella-zoster virus (VZV), and tetanus toxoid in normal controls, long-term nonprogressors (LTNP), and HIV-infected patients with progressive disease on or off therapy. The HIV-specific CD4+ T-cell responses in LTNP and patients on therapy were similar in frequency, phenotype, and cytokine production to responses directed against adenovirus, EBV, influenza virus, and VZV. HIV-specific CD4+ T cells from patients off antiretroviral therapy demonstrated a shift towards a CCR7− CD45RA− phenotype and a reduced percentage of IL-2-producing cells. The alterations in cytokine production during HIV viremia were found to be intrinsic to the HIV-specific CD4+ T cells and caused a requirement for IL-2 supplied exogenously for proliferation to occur. These observations suggest that many previously described changes in HIV-specific CD4+ T-cell function and phenotype are a consequence of high levels of antigen in viremic patients. In addition, defects in function and phenotype of HIV-specific CD4+ T cells are not readily discernible in the context of antiretroviral therapy but rather are similar to responses to other viruses.

scholarly journals HIV Controllers with HLA-DRB1*13 and HLA-DQB1*06 Alleles Have Strong, Polyfunctional Mucosal CD4+ T-Cell Responses

2010 ◽  
Vol 84 (21) ◽  
pp. 11020-11029 ◽  
Author(s):  
April L. Ferre ◽  
Peter W. Hunt ◽  
Delandy H. McConnell ◽  
Megan M. Morris ◽  
Juan C. Garcia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Rectal Mucosa ◽  
T Cell Responses ◽  
Class Ii ◽  
T Cell Response ◽  
Cell Responses ◽  
Hiv Controllers

ABSTRACT A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 “controllers” (viral load [VL] of <2,000 copies/ml), 14 “noncontrollers” (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher-magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P < 0.05), as measured by their ability to produce gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1β (MIP-1β). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearman's r = 0.43, P = 0.005), suggesting that increased CD4+ T-cell “help” may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers.

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