scholarly journals Dynamics of killer T cell inflation in viral infections

2006 ◽  
Vol 4 (14) ◽  
pp. 533-543 ◽  
Author(s):  
Dominik Wodarz ◽  
Sophie Sierro ◽  
Paul Klenerman
Keyword(s):  
Experimental Data ◽  
Cell Response ◽  
Nk Cell ◽  
Cytotoxic T Lymphocyte ◽  
Acute Infection ◽  
Murine Cytomegalovirus ◽  
Ctl Response ◽  
Virus Load ◽  
The Impact ◽  
Over Time

Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is characterized by a phase of expansion and contraction after which it settles at a relatively stable memory level. Recently, experimental data from mice infected with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After acute infection had resolved, some antigen specific CTL started to expand over time despite the fact that no replicative virus was detectable. This phenomenon has been termed as ‘CTL memory inflation’. In order to examine the dynamics of this system further, we developed a mathematical model analysing the impact of innate and adaptive immune responses. According to this model, a potentially important contributor to CTL inflation is competition between the specific CTL response and an innate natural killer (NK) cell response. Inflation occurs most readily if the NK cell response is more efficient than the CTL at reducing virus load during acute infection, but thereafter maintains a chronic virus load which is sufficient to induce CTL proliferation. The model further suggests that weaker NK cell mediated protection can correlate with more pronounced CTL inflation dynamics over time. We present experimental data from mice infected with MCMV which are consistent with the theoretical predictions. This model provides valuable information and may help to explain the inflation of CMV specific CD8+T cells seen in humans as they age.

scholarly journals The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 866
Author(s):  
Baca Chan ◽  
Maja Arapović ◽  
Laura Masters ◽  
Francois Rwandamuiye ◽  
Stipan Jonjić ◽  
...  
Keyword(s):  
Nk Cells ◽  
Salivary Glands ◽  
Natural Killer ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
Viral Escape ◽  
Murine Cytomegalovirus ◽  
Viral Shedding ◽  
Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

scholarly journals Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus

2000 ◽  
Vol 191 (9) ◽  
pp. 1499-1512 ◽  
Author(s):  
Franziska Lechner ◽  
David K.H. Wong ◽  
P. Rod Dunbar ◽  
Roger Chapman ◽  
Raymond T. Chung ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Acute Infection ◽  
Hcv Infection ◽  
Ctl Response ◽  
Acute Hcv ◽  
Ifn Γ ◽  
Acute Hcv Infection

Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a “stunned” phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.

scholarly journals The Role of NKG2D Signaling in Inhibition of Cytotoxic T-Lymphocyte Lysis by the Murine Cytomegalovirus Immunoevasin m152/gp40

2007 ◽  
Vol 81 (22) ◽  
pp. 12564-12571 ◽  
Author(s):  
Amelia K. Pinto ◽  
Amanda M. Jamieson ◽  
David H. Raulet ◽  
Ann B. Hill
Keyword(s):  
Mhc Class I ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Small Subset ◽  
Small Contribution ◽  
Nkg2d Ligands ◽  
Infected Cells ◽  
The Impact

ABSTRACT Three proteins encoded by murine cytomegalovirus (MCMV)— gp34, encoded by m04 (m04/gp34), gp48, encoded by m06 (m06/gp48), and gp40, encoded by m152 (m152/gp40)—act together to powerfully impact the ability of primed cytotoxic CD8 T lymphocytes (CTL) to kill virus-infected cells. Of these three, the impact of m152/gp40 on CTL lysis appears greater than would be expected based on its impact on cell surface major histocompatibility complex (MHC) class I. In addition to MHC class I, m152/gp40 also downregulates the RAE-1 family of NKG2D ligands, which can provide costimulation for CD8 T cells. We hypothesized that m152/gp40 may impact CTL lysis so profoundly because it inhibits both antigen presentation and NKG2D-mediated costimulation. We therefore tested the extent to which m152/gp40's ability to inhibit CTL lysis of MCMV-infected cells could be accounted for by its inhibition of NKG2D signaling. As was predictable from the results reported in the literature, NKG2D ligands were not detected by NKG2D tetramer staining of cells infected with wild-type MCMV, whereas those infected with MCMV lacking m152/gp40 displayed measurable levels of the NKG2D ligand. To determine whether NKG2D signaling contributed to the ability of CTL to lyse these cells, we used a blocking anti-NKG2D antibody. Blocking NKG2D signaling did affect the killing of MCMV-infected cells for some epitopes. However, for all epitopes, the impact of m152/gp40 on CTL lysis was much greater than the impact of inhibition of NKG2D signaling. We conclude that the downregulation of NKG2D ligands by MCMV makes only a small contribution to the impact of m152/gp40 on CTL lysis and only for a small subset of CTL.

scholarly journals Lentivirus-Specific Cytotoxic T-Lymphocyte Responses Are Rapidly Lost in Thymectomized Cats Infected with Feline Immunodeficiency Virus

2005 ◽  
Vol 79 (13) ◽  
pp. 8237-8242 ◽  
Author(s):  
Kathleen A. Hayes ◽  
Sadi Köksoy ◽  
Andrew J. Phipps ◽  
Wayne R. Buck ◽  
Gary J. Kociba ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Feline Immunodeficiency Virus ◽  
Cytotoxic T Lymphocyte ◽  
Significant Loss ◽  
Ctl Response ◽  
Virus Load ◽  
Immunodeficiency Virus ◽  
Plasma Virus Load ◽  
Lymphocyte Responses ◽  
Ctl Responses

ABSTRACT To what extent the thymus is needed to preserve the virus-specific cytotoxic T-lymphocyte (CTL) response of lentivirus-infected adults is unclear. Presented here is the first definitive study using thymectomized (ThX) animals to directly evaluate the contribution of thymic function to lentivirus-specific CTL response and the control of lentivirus infections. ThX and mock-ThX cats were inoculated with feline immunodeficiency virus (FIV) and monitored for their FIV-specific CTL responses. Early in infection, both FIV-ThX and FIV-mock-ThX cats produced similar CTL responses, but surprisingly, after 20 weeks, the FIV-ThX cats showed a statistically significant loss of FIV-specific CTL activity, while FIV-infected cats with intact thymuses continued to maintain FIV-specific CTL. The loss of CTL did not affect plasma virus load, which remained elevated for both groups. These results emphasize the importance of thymic integrity in maintaining immunity to lentiviruses, but also bring into question the notion that virus load is regulated predominantly by the virus-specific CTL response.

scholarly journals Correlates of cytotoxic T–lymphocyte–mediated virus control: implications for immuno–suppressive infections and their treatment

2000 ◽  
Vol 355 (1400) ◽  
pp. 1059-1070 ◽  
Author(s):  
Dominik Wodarz ◽  
Martin A. Nowak
Keyword(s):  
Viral Replication ◽  
Mathematical Models ◽  
Cytotoxic T Lymphocyte ◽  
Hiv Persistence ◽  
Ctl Response ◽  
Virus Load ◽  
Memory Response ◽  
Immunodeficiency Virus ◽  
The Relationship

A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarizes how mathematical models help us gain new insights into these questions, and explores the relationship between antiviral therapy and long–term immunological control in human immunodeficiency virus (HIV) infection. We find that cytotoxic Tlymphocyte (CTL) memory, defined as antigen–independent persistence of CTL precursors, is necessary for the CTL response to clear an infection. The presence of such a memory response is associated with the coexistence of many CTL clones directed against multiple epitopes. If CTL memory is inefficient, then persistent replication can be established. This outcome is associated with a narrow CTL response directed against only one or a few viral epitopes. If the virus replicates persistently, occurrence of pathology depends on the level of virus load at equilibrium, and this can be determined by the overall efficacy of the CTL response. Mathematical models suggest that controlled replication is reflected by a positive correlation between CTLs and virus load. On the other hand, uncontrolled viral replication results in higher loads and the absence of a correlation between CTLs and virus load. A negative correlation between CTLs and virus load indicates that the virus actively impairs immunity, as observed with HIV. Mathematical models and experimental data suggest that HIV persistence and pathology are caused by the absence of sufficient CTL memory. We show how mathematical models can help us devise therapy regimens that can restore CTL memory in HIV patients and result in long–term immunological control of the virus in the absence of life–long treatment.

scholarly journals Dissection of the NKG2C NK cell response against Puumala Orthohantavirus

2021 ◽  
Vol 15 (12) ◽  
pp. e0010006
Author(s):  
Hannes Vietzen ◽  
Svenja Hartenberger ◽  
Stephan W. Aberle ◽  
Elisabeth Puchhammer-Stöckl
Keyword(s):  
Nk Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Nk Cell ◽  
Hemorrhagic Fever ◽  
Substantial Impact ◽  
Cell Responses ◽  
Infected Cells ◽  
The Impact

Background Infections with the Puumala orthohantavirus (PUUV) in humans may cause hemorrhagic fever with renal syndrome (HFRS), known as nephropathia epidemica (NE), which is associated with acute renal failure in severe cases. In response to PUUV-infections, a subset of potent antiviral NKG2C+ NK cells expand, whose role in virus defence and pathogenesis of NE is unclear. NKG2C+ NK cell proliferation is mediated by binding of NKG2C/CD94 to HLA-E on infected cells. The proliferation and activation of NKG2C+ NK cells via the NKG2C/HLA-E axis is affected by different NKG2C (NKG2Cwt/del) and HLA-E (HLA-E*0101/0103) alleles, which naturally occur in the human host. Homozygous (NKG2Cdel/del) and heterozygous (NKG2Cwt/del) deletions of the NKG2C receptor results in an impaired NKG2C/CD94 mediated proliferation and activation of NKG2C+ cells. We therefore analyzed the PUUV-mediated NKG2C+ NK cell responses and the impact of different NKG2C and HLA-E alleles in NE patients. Methodology/Principal findings NKG2C+ NK cell expansion and effector functions in PUUV-infected cells were investigated using flow cytometry and it was shown that PUUV-infected endothelial cells led to a NKG2C/CD94 mediated NKG2C+ NK cell activation and expansion, dependent on the HLA-G-mediated upregulation of HLA-E. Furthermore, the NKG2Cdel and HLA-E*0101/0103 alleles were determined in 130 NE patients and 130 matched controls, and it was shown that in NE patients the NKG2Cwt/del allele was significantly overrepresented, compared to the NKG2Cwt/wt variant (p = 0.01). In addition, in vitro analysis revealed that NKG2Cwt/del NK cells exhibited on overall a lower proliferation (p = 0.002) and lower IFNγ expression (p = 0.004) than NKG2Cwt/wt NK cells. Conclusions/Significance Our results corroborate the substantial impact of the NKG2C/HLA-E axis on PUUV-specific NK cell responses. A weak NKG2C+ NK cell response, as reflected by NKG2Cwt/del variant, may be associated with a higher risk for a severe hantavirus infections.

scholarly journals Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2665-2674 ◽  
Author(s):  
Bree Foley ◽  
Sarah Cooley ◽  
Michael R. Verneris ◽  
Michelle Pitt ◽  
Julie Curtsinger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
First Year ◽  
Cmv Infection ◽  
Cmv Reactivation

AbstractDuring mouse cytomegalovirus (CMV) infection, a population of Ly49H+ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a “memory NK-cell response.” Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C+ NK cells expanded and were potent producers of IFNγ. NKG2C+ NK cells predominately expressed killer cell immunoglobulin–like receptor, and self-killer cell immunoglobulin–like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells. Strikingly, increased frequencies of NKG2C+ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C+ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.

scholarly journals The Virus-Specific and Allospecific Cytotoxic T-Lymphocyte Response to Lymphocytic Choriomeningitis Virus Is Modified in a Subpopulation of CD8+ T Cells Coexpressing the Inhibitory Major Histocompatibility Complex Class I Receptor Ly49G2

2000 ◽  
Vol 74 (15) ◽  
pp. 7032-7038 ◽  
Author(s):  
Craig D. Peacock ◽  
Meei Y. Lin ◽  
John R. Ortaldo ◽  
Raymond M. Welsh
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Nk Cell ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Ctl Response

ABSTRACT The role of negatively signaling NK cell receptors of the Ly49 family on the specificity of the acute CD8+ cytotoxic T-lymphocyte (CTL) response was investigated in lymphocytic choriomeningitis virus (LCMV)-infected C57BL/6 mice. Activated CD8+ T cells coexpressing Ly49G2 expanded during LCMV infection, and T-cell receptor analyses by flow cytometry and CDR3 spectratyping revealed a unique polyclonal T-cell population in the Ly49G2+ fraction. These cells lysed syngeneic targets infected with LCMV or coated with two of three LCMV immunodominant peptides examined. Transfection of these sensitive targets with H2Dd, a ligand for Ly49G2, inhibited lysis. This was reversed by antibody to Ly49G2, indicating effective negative signaling. LCMV characteristically induces an anti-H2dallospecific T-cell response that includes T-cell clones cross-reactive between allogeneic and LCMV-infected syngeneic targets. The CD8+ Ly49G2+ population mediated no allospecific killing, nor was any NK-like killing observed against YAC-1 cells. This study shows that CD8+ Ly49G2+cells participate in the virus-induced CTL response but lyse a more restricted range of targets than the rest of the virus-induced CTL population.

The Therapist’s Reaction to a Patient’s Suicide

Crisis ◽  
2011 ◽  
Vol 32 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Friedrich Martin Wurst ◽  
Isabella Kunz ◽  
Gregory Skipper ◽  
Manfred Wolfersdorf ◽  
Karl H. Beine ◽  
...  
Keyword(s):  
Emotional Responses ◽  
Well Being ◽  
Emotional Reaction ◽  
Emotional Reactions ◽  
Analog Scale ◽  
General Hospitals ◽  
Item Questionnaire ◽  
Retrospective Nature ◽  
The Impact ◽  
Over Time

Background: A substantial proportion of therapists experience the loss of a patient to suicide at some point during their professional life. Aims: To assess (1) the impact of a patient’s suicide on therapists distress and well-being over time, (2) which factors contribute to the reaction, and (3) which subgroup might need special interventions in the aftermath of suicide. Methods: A 63-item questionnaire was sent to all 185 Psychiatric Clinics at General Hospitals in Germany. The emotional reaction of therapists to patient’s suicide was measured immediately, after 2 weeks, and after 6 months. Results: Three out of ten therapists suffer from severe distress after a patients’ suicide. The item “overall distress” immediately after the suicide predicts emotional reactions and changes in behavior. The emotional responses immediately after the suicide explained 43.5% of the variance of total distress in a regression analysis. Limitations: The retrospective nature of the study is its primary limitation. Conclusions: Our data suggest that identifying the severely distressed subgroup could be done using a visual analog scale for overall distress. As a consequence, more specific and intensified help could be provided to these professionals.

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