scholarly journals Localization of Viral Epitope-Specific CD8 T Cells during Cytomegalovirus Latency in the Lungs and Recruitment to Lung Parenchyma by Airway Challenge Infection

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 918
Author(s):  
Franziska Blaum ◽  
Dominika Lukas ◽  
Matthias J. Reddehase ◽  
Niels A. W. Lemmermann
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Alveolar Epithelium ◽  
Challenge Infection ◽  
Murine Cytomegalovirus ◽  
Effector Memory ◽  
Memory Cells ◽  
Viral Epitope ◽  
Effector Memory Cells

Interstitial pneumonia is a life-threatening clinical manifestation of cytomegalovirus infection in recipients of hematopoietic cell transplantation (HCT). The mouse model of experimental HCT and infection with murine cytomegalovirus revealed that reconstitution of virus-specific CD8+ T cells is critical for resolving productive lung infection. CD8+ T-cell infiltrates persisted in the lungs after the establishment of latent infection. A subset defined by the phenotype KLRG1+CD62L− expanded over time, a phenomenon known as memory inflation (MI). Here we studied the localization of these inflationary T effector-memory cells (iTEM) by comparing their frequencies in the intravascular and transmigration compartments, the IVC and TMC, respectively, with their frequency in the extravascular compartment (EVC), the alveolar epithelium. Frequencies of viral epitope-specific iTEM were comparable in the IVC and TMC but were reduced in the EVC, corresponding to an increase in KLRG1−CD62L− conventional T effector-memory cells (cTEM) and a decrease in functional IFNγ+CD8+ T cells. As maintained expression of KLRG1 requires stimulation by antigen, we conclude that iTEM lose KLRG1 and convert to cTEM after transmigration into the EVC because pneumocytes are not latently infected and, therefore, do not express antigens. Accordingly, antigen re-expression upon airway challenge infection recruited virus-specific CD8+ T cells to TMC and EVC.

CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

2007 ◽  
Vol 37 (12) ◽  
pp. 3352-3362 ◽  
Author(s):  
Máire F. Quigley ◽  
Veronica D. Gonzalez ◽  
Anna Granath ◽  
Jan Andersson ◽  
Johan K. Sandberg
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Effector Memory Cells

Analysis Of Circulating Rhinovirus-Specific CD4+ T Cells Using Novel MHC Class II Tetramers Reveals Marked Expansion Of Effector Memory Cells In Infected Subjects

2014 ◽  
Vol 133 (2) ◽  
pp. AB292
Author(s):  
Lyndsey Muehling ◽  
Rachana Agrawal ◽  
Julia Wisniewski ◽  
Paul Wright ◽  
William W. Kwok ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Effector Memory ◽  
Memory Cells ◽  
Effector Memory Cells

Index of Bone Marrow Output and Imbalance of B-Lymphocyte Homeostasis before and after Transplantation Correlate Differently with Graft-Versus-Host Disease and Relapse

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3150-3150
Author(s):  
Crisitina Skert ◽  
Simone Perucca ◽  
Imberti Luisa ◽  
Chiarini Marco ◽  
Michele Malagola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Effector Memory ◽  
Memory Cells ◽  
Immunological Parameters ◽  
Immature B Cells ◽  
Effector Memory Cells

Abstract Introduction The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in SCT. Researches on GVHD-biomarkers are still ongoing and a set of validate markers are still lacking, especially for chronic GVHD. Furthermore, immune parameters that univocally associate with GVHD or GVT have not been identified yet. In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of GVHD and ineffective GVT. Methods Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients. Results Twenty patients developed acute GVHD (median time: 28 days, range 19-120). Chronic GVHD was observed in 9 patients (median time: 6 months, range 4-10). In multivariate analysis, acute GVHD correlated positively with pre-transplant percentage of CD4+ central memory cells, and with values of regulatory effector memory T-cells and CD4+TEMRA cell at day +30 (p=0,0006). Pre-transplant percentage of unswitched memory B cells was also associated with acute GVHD, whereas pre-transplant levels of KRECs were inversely correlated (p=0,0005). Chronic GVHD was associated with matched unrelated donor and with (p<0,05): -values of regulatory effector memory T-cells at +30, percentage of CD8+TEMRA cells at +90, values of immature B cells and levels of KRECs at +180 (positive correlation) -percentage of CD4+ central memory and CD8+ effector memory cells at +90 (negative correlation). The relapse rate (27%; median time: 5,5 months, range 3-12) was used as clinical index of ineffective GVT. The following cluster of immunological parameters at day +90 correlated positively with relapse: CD8+ effector memory cells, immature B cells, naïve, switched memory B cells, memory double negative (IgD-CD27-) B cells (p=0,006). Discussion Different clusters of immunological parameters at different time points were evidenced as predictors of GVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and specific imbalances in the subset of B-cells may be involved in acute and chronic GVHD development. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>effector memory), as shown in some experimental models. Increased values of CD8+ effector memory cells could be an early sign of ineffective GVL. Imbalance toward a lymphocyte B-response, and especially toward "senescent" memory (IgD-CD27-) B cells, could promote tolerance to tumor cells. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

2009 ◽  
Vol 83 (19) ◽  
pp. 10293-10298 ◽  
Author(s):  
Verena Böhm ◽  
Christof K. Seckert ◽  
Christian O. Simon ◽  
Doris Thomas ◽  
Angélique Renzaho ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Effector Memory ◽  
Viral Gene ◽  
Cmv Infection ◽  
Hematopoietic Reconstitution ◽  
Latently Infected ◽  
Effector Memory Cells

ABSTRACT CD8 T cells control cytomegalovirus (CMV) infection in bone marrow transplantation recipients and persist in latently infected lungs as effector memory cells for continuous sensing of reactivated viral gene expression. Here we have addressed the question of whether viral immunoevasins, glycoproteins that specifically interfere with antigen presentation to CD8 T cells, have an impact on viral latency in the murine model. The data show that deletion of immunoevasin genes in murine CMV accelerates the clearance of productive infection during hematopoietic reconstitution and leads to a reduced latent viral genome load, reduced latency-associated viral transcription, and a lower incidence of recurrence in lung explants.

scholarly journals Lipopolysaccharide Increases Immune Activation and Alters T Cell Homeostasis in SHIVB’WHUChronically Infected Chinese Rhesus Macaque

2015 ◽  
Vol 2015 ◽  
pp. 1-13
Author(s):  
Gao-Hong Zhang ◽  
Run-Dong Wu ◽  
Hong-Yi Zheng ◽  
Xiao-Liang Zhang ◽  
Ming-Xu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Effector Memory ◽  
Memory Cells ◽  
T Cell Homeostasis ◽  
Programmed Cell Death 1 ◽  
Effector Memory Cells ◽  
Lymphocyte Homeostasis ◽  
Chinese Rhesus Macaques

Immune activation plays a significant role in the disease progression of HIV. Microbial products, especially bacterial lipopolysaccharide (LPS), contribute to immune activation. Increasing evidence indicates that T lymphocyte homeostasis disruptions are associated with immune activation. However, the mechanism by which LPS affects disruption of immune response is still not fully understood. Chronically SHIVB’WHU-infected Chinese rhesus macaques received 50 μg/kg body weight LPS in this study. LPS administration affected the virus/host equilibrium by elevating the levels of viral replication and activating T lymphocytes. LPS induced upregulation of CD8+naïve T cells and downregulated the number of CD4+and CD8+T effector memory cells. The downregulated effector memory cells are associated with a lower frequency of monofunctional and polyfunctional cells, and an upregulated programmed cell death-1 (PD-1) expression on CD4+and CD8+T cells was observed in monkeys after LPS stimulation. Our data provide new insights into the function of LPS in the immune activation in SHIV/HIV infection.

scholarly journals CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential

2021 ◽  
Vol 11 ◽  
Author(s):  
Vanaja Konduri ◽  
Damilola Oyewole-Said ◽  
Jonathan Vazquez-Perez ◽  
Scott A. Weldon ◽  
Matthew M. Halpert ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Cell Subset ◽  
Effector Memory ◽  
Memory Cells ◽  
Mait Cells ◽  
Effector Memory Cells

NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

Allosensitized Memory CD4 T Cells Induce Chronic Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Suparna Dutt ◽  
Diane Tseng ◽  
Tracy I. George ◽  
Joerg Ermann ◽  
Yinping Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Mouse Bone Marrow ◽  
Memory Cells ◽  
Activation Markers ◽  
Effector Memory Cells ◽  
Memory Cd4 T Cells

Abstract It has been reported that naive CD4+CD62LhiCD44lo T cells induce severe GVHD in a complete MHC mismatched allogeneic model of mouse bone marrow transplantation (BMT), but that effector memory CD4+CD62LloCD44hi T cells obtained from normal donors do not induce GVHD. The lack of GVHD-inducing capacity of effector memory cells from unprimed donors may reflect their lack of previous exposure to host alloantigens. We tested this hypothesis in a complete MHC mismatched allogeneic model of BMT by comparing the ability of effector memory T cells obtained from untreated C57BL/6 donors and donors immunized against host BALB/C alloantigens to induce GVHD. C57BL/6 donors were immunized by injecting 50 x106 host BALB/C spleen cells i.p. and after one week with 10x 106 cells. Both the unprimed and alloantigen primed CD4+ T cells expressed similar levels of lymph node homing chemokine receptor CCR7, and activation markers like CD69 and CD25. We sorted naive (CD62LhiCD44lo) and effector memory (CD62LloCD44hi) CD4+ T cell subsets from C57BL/6 donor mice four weeks after immunization, and compared their alloreactivity to BALB/C in an in vitro MLR. Interestingly effector memory CD4+ T cells from primed mice produced significantly higher levels of IFNγ compared to the effector memory from unprimed donors. We found that CD62LloCD44hi cells from unimmunized donors failed to induce GVHD in 85% of the hosts over 100 days while CD62LloCD44hi cells from immunized donors caused progressive weight loss and death in 100% of hosts (p &lt;0.001). Whereas naive CD4+ T cells from unimmunized donors accumulated rapidly in the lymph nodes and spleen of irradiated hosts, effector memory CD4+ T cells had markedly reduced accumulation in these tissues. Furthermore, at day 6 after transplantation effector memory CD4+ T cells from primed mice, showed hundred fold higher accumulation in the host liver compared to unprimed effector memory donor CD4+ T cells. Long term surviving hosts transplanted with primed effector memory cells showed histopathological features of chronic GVHD in liver characterized by portal tract inflammation and lymphocyte infiltration with bile duct injury. In conclusion, memory CD4+ T cells from donors immunized to host alloantigens are able to induce chronic GVHD , but memory cells from unimmunized donors do not.

The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1216-1216
Author(s):  
Rinat Rotem-Yehudar ◽  
Philippe Armand ◽  
Steve Devine ◽  
Joseph W. Fay ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
B Cell Lymphoma ◽  
Peripheral Tolerance ◽  
Effector Memory ◽  
Memory Cells ◽  
Antibody Treatment ◽  
Effector Memory Cells ◽  
Memory T Lymphocytes ◽  
Memory Lymphocytes

Abstract Abstract 1216 Poster Board I-238 Background: PD-1 (Program Death-1), an immune inhibitory receptor and its ligands PD-L1 and PD-L2, participate in peripheral tolerance and play a key role in immune suppression and evasion mechanisms in cancer and chronic infectious diseases. PD-1 inhibits activation signals and functions as a pro-apoptotic receptor in effector lymphocytes, and consequently regulates the extent and duration of specific adaptive and innate immune responses. CT-011, a humanized antibody, blocks the function of PD-1, resulting in increased activities of T and NK cells in vitro and in enhanced tumor immunity in experimental tumor models. At the molecular level, the antibody enhances PI3K-mediated survival and trafficking signals, attenuates cell death in effector/memory (CD4+CD45RO+) cells, and enhances trafficking in response to Stromal Cell-derived Factor-1 (SDF-1). We hypothesized that CT-011 would enhance effector/memory cells in patients with DLBCL after AuSCT and delay recurrence. Methods: We treated 41 patients (pts) with DLBCL from 30-90 days after AuSCT with CT-011 and now report data on effector/memory and memory lymphocytes in the first 30 pts. CT-011 was given at a dose of 1.5mg/kg for 3 doses, 6 weeks apart. The primary endpoint was to determine the proportion of patients who have not relapsed or died within 18 months following autologous PBSCT, and it is too early for that analysis. Our secondary endpoint was to measure the number of effector /memory and memory lymphocytes before and after treatment, and those data are the subject of this report. Results: Flow cytometry analyses (Table) on pre (baseline: BL) and post-treatment blood samples from the first 30 pts enrolled show elevated levels of specific effector/memory and memory CD4+ T lymphocytes following treatment with CT-011; the median absolute number (ABS) of effector/memory CD4+CD45RO+CD62L-CCR7- cells was increased by +49% from BL (p<0.05) 6 weeks following the first treatment with CT-011, reaching a 2 fold increase in the ABS levels from BL and a 45% increase in the median percentage of the total lymphocyte population (p<0.05) 4 weeks after the third antibody treatment (week 16). The percentage of peripheral memory CD4+ CD62L-CD127+ cells was also increased by 61% from BL (median, p<0.05) on week 16. The observed increase, particularly of the effector/memory CD4+CD45RO+CD62L-CCR7- lymphocytes, a subset directly linked to PD-1 activity and to tumor immune surveillance, likely indicates a specific cellular response to CT-011, since no significant changes were observed for other memory cell subsets including CD4+CD45RO+CD62L+CCR7+cells, CD4+ CD62L+CD127+ cells, CD8+ CD62L-CD127+, CD8+CD62L+CD127+ cells or CD4+CD25+ FOXP3+ suppressor T cells. Overall no changes were observed in the level of total lymphocytes or T cells throughout 16 weeks of follow up from the 1st antibody treatment. Transient reduction of 32% (median, p<0.05) and 25% (median, p<0.05) in the ABS levels of CD3+CD8+ and CD3+CD45RO+, respectively, was observed at week 12, which recovered to baseline or higher levels on week 16. These changes may be explained by trafficking or recycling of CD8+ effector/memory cells from the periphery to target organs. Conclusions: Consistent with its mechanism of action, CT-011 increases the levels of specific CD4+ effector/memory and memory T lymphocytes. This is the first demonstration of safe induction of effector memory and memory lymphocytes, essential components of tumor- immune control, in lymphoma patients following AuSCT. This antibody may have promise for the treatment of lymphoma. Disclosures: Rotem-Yehudar: Cure Tech: Employment. Gordon:Cure Tech: Membership on an entity's Board of Directors or advisory committees.

Patterns of Lymphocyte Subsets and Index of Bone Marrow Output (KRECs) Correlate Differently with Graft-Versus-Host Disease and Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3933-3933
Author(s):  
Cristina Skert ◽  
Simone Perucca ◽  
Luisa Imberti ◽  
Marco Chiarini ◽  
Michele Malagola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Median Time ◽  
Chronic Gvhd ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Immunological Parameters ◽  
Effector Memory Cells

Abstract Introduction. Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative option for several haematological diseases. Its efficacy relies primarily on the Graft-versus-tumor (GVT) effect, which is promoted by donor immune cells. However, GVT partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in HSCT, since they may share immune effector cells and antigen targets, such as minor histocompatibility antigens. The development of a functional immune system is one of the main factors influencing the clinical outcome of HSCT. Immune deficiency as well as the effect of GVT/GvHD imbalance can expose patients to a high risk of opportunistic infections and disease relapse. Many studies analyzed immune reconstitution after HSCT both retrospectively and prospectively. However, immune parameters that univocally associate with GVHD or GVT have not been identified yet. In this study, lymphocyte subsets together with index of thymic and bone marrow output were evaluated at different time points, in order to identify possible indicators/predictors of GVHD and ineffective GVT. Methods. Prospective evaluations of immune reconstitution were performed in 37 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients. Results. Twelve patients developed acute GVHD (median time: 28 days, range 17-120). Chronic GVHD was observed in 8 patients (median time: 6 months, range 4-8). In multivariate analysis, acute GVHD correlated positively with values of regulatory central memory T-cells (HR 1, 24; p=0,0006) and negatively with values of regulatory naïve T-cells (HR 0,52; p=0,006) at day +30. CD4+ effector memory T-cells at day +90 were positively associated with chronic GVHD (HR 1,3; p=0,04). The relapse rate (27%; median time: 5,5 months, range 3-12) was used as clinical index of ineffective GVT. The following cluster of immunological parameters at day +90 correlated positively with relapse: CD8+ effector memory cells, immature B cells, mature, naïve, switched memory B cells, memory double negative (IgD-CD27-) B cells, and KRECs (HR 2,4; p=0,006). Discussion Different clusters of immunological parameters were evidenced as predictors of GVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. The non-univocal association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>central memory regulatory), as shown in some experimental models. Increased values of CD8+ effector memory cells could be an early sign of ineffective GVL. Imbalance toward a lymphocyte B-response, and especially toward “senescent” memory (IgD-CD27-) B cells, could promote tolerance to tumor cells. The validation of these clusters of immunological parameters as specific early indicators of GVHD or GVT could potentially allow the development of pre-emptive and targeted therapies. Disclosures No relevant conflicts of interest to declare.

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