scholarly journals Age-Specific Imbalance of Circulating Tfh Cell Subsets and Its Association With Gout-Targeted Kidney Impairment

2021 ◽  
Vol 11 ◽  
Author(s):  
Yefei Huang ◽  
Xinyu Wu ◽  
Lian Gui ◽  
Yutong Jiang ◽  
Liudan Tu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Renal Dysfunction ◽  
Clinical Features ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Color Flow ◽  
B Cell Subsets

ObjectiveGout is a chronic disease characterized by the deposition of monosodium urate (MSU) crystals in tissue. Study with a focus on adaptive immune response remains to be understood although innate immune response has been reported extensively in gout etiology. Our study attempted to investigate the association of gout-related immune cell imbalance with clinical features and comorbidity with renal impairment and the implicated pathogenesis via the assessment of T and B cell subsets in different activity phases or with immune effects combined with the analyses of clinical parameters.MethodsFifty-eight gout patients and 56 age- and sex-matched healthy individuals were enrolled. To learn the roles of circulating T cells, a lymphocyte profile incorporating 32 T cell subsets was tested from isolated freshly peripheral blood monocyte cells (PBMCs) with multiple-color flow cytometry. Furthermore, the collected clinical features of participants were used to analyze the characteristics of these differential cell subsets. Stratified on the basis of the level of creatinine (Cr, enzymatic method), all patients were categorized into Crlow (Cr ≤ 116 μmol/L) and Crhi (Cr > 116 μmol/L) groups to exploit whether these gout-associated T cell subsets were functional in gout-targeted kidney dysfunction. The differentiation of B cells was investigated in gout patients.ResultsOur results show that CD 4+ T cells, Th2 cells, and Tc2 cells were upregulated, whereas Tc17 cells were downregulated. Tfh cells skewed toward the polarization of Tfh2 cells. Specifically, Tfh2 cells increased, but Tfh1 cells decreased, accompanied with aging for gout patients, suggesting that age might trigger the skewing of Tfh1/Tfh2 cell subsets to influence gout development. Moreover, Tfh2 cells were connected to renal dysfunction as well. No alterations of B cell subsets were observed in patients when compared to controls.ConclusionsOur data demonstrate age-specific dysfunctions of Tfh1/2 cells in gout occurrence, and Tfh2 cell upregulation is associated with gout-targeted renal dysfunction. However, Tfh2 cells may function in auto-inflammatory gout independent of helping B differentiation, and an in-depth study remains to be conducted.

scholarly journals Characterization of CD4-Positive Lymphocytes in the Antiviral Response of Olive Flounder (Paralichthys oliveceus) to Nervous Necrosis Virus

2020 ◽  
Vol 21 (11) ◽  
pp. 4180
Author(s):  
Jae Wook Jung ◽  
Jin Hong Chun ◽  
Jung Seok Lee ◽  
Si Won Kim ◽  
Ae Rin Lee ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Viral Infection ◽  
T Cell Subsets ◽  
Olive Flounder ◽  
Flow Cytometry Analysis ◽  
Color Flow

The presence of CD4 T lymphocytes has been described for several teleost species, while many of the main T cell subsets have not been characterized at a cellular level, because of a lack of suitable tools for their identification, e.g., monoclonal antibodies (mAbs) against cell markers. We previously described the tissue distribution and immune response related to CD3ε and CD4-1 T cells in olive flounder (Paralichthys oliveceus) in response to a viral infection. In the present study, we successfully produce an mAb against CD4-2 T lymphocytes from olive flounder and confirmed its specificity using immuno-blotting, immunofluorescence staining, flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR). Using these mAbs, we were able to demonstrate that the CD3ε T cell populations contain both types of CD4+ cells, with the majority of the CD4 T cell subpopulations being CD4-1+/CD4-2+ cells, determined using two-color flow cytometry analysis. We also examined the functional activity of the CD4-1 and CD4-2 cells in vivo in response to a viral infection, with the numbers of both types of CD4 T cells increasing significantly during the virus infection. Collectively, these findings suggest that the CD4 T lymphocytes in olive flounder are equivalent to the helper T cells in mammals in terms of their properties and function, and it is the CD4-2 T lymphocytes rather than the CD4-1 T cells that play an important role in the Th1 immune response against viral infections in olive flounder.

scholarly journals POS0003 RITUXIMAB THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS – TRANSIENT EFFECTS ON AGE ASSOCIATED B-CELLS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 203.1-204
Author(s):  
F. Faustini ◽  
N. Sippl ◽  
R. Stålesen ◽  
K. Chemin ◽  
I. Gunnarsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Subsets ◽  
Cd4 Cells ◽  
Helper Cells ◽  
B Cell Subsets ◽  
Anti Cd20

Background:Immune system’s abnormalities in SLE involve several subsets of the B-cell compartment, including double negative B-cells (DN) and CD11c+CD21- B cells (also referred to as ABC-age associated B cells), which are expanded in the disease. ABC cells are also known to interact with T helper cells, T follicular and peripheral helper cells (1). Rituximab, a chimeric anti- CD20 antibody, depleting B cells, is commonly used off-label as treatment for SLE patients, especially in lupus nephritis. Little is known on the impact of B-cell depletion on such B-cell subsets and on B-T-cell interactions.Objectives:to investigate the effects of rituximab (RTX) on the frequencies of double negative B-cell subsets and CD11c+CD21- ABC cells and as well as T follicular helper (TFH, CXCR5+ PD-1+) and T peripheral helper (TPH, PD-1high) CD4+ T-cell subsets.Methods:15 SLE patients, starting RTX and followed longitudinally up to two years, were analyzed for lymphocyte subsets using multicolor flow cytometry. Cryopreserved PBMC were thawed and stained at the same time together with one buffy coat. Around 1 x 106 PBMC for each panel were labeled and further stained with fluorescent antibodies for B and T-cell markers. For the B-cell panel, PBMC were stained with anti-CD3, CD14, CD16, CD19, IgD, CD27, CD38, CD11c, CD21 and in some samples with anti-CXCR5 antibodies. For the T-cell panel, PBMC were labeled with anti-CD16, CD14, CD19 and CD3, CD4, CD8, PD-1, CCR7, CXCR5, CD45RA antibodies. All patients fulfilled the ACR 1982 classification criteria for SLE. Cellular changes were analyzed in the context of clinical information.Results:in the present cohort, the SLE patients were mainly female (86.6%) and of median age of 36.7 (29.8-49.4) with a disease duration of 6.1(1.6-11.8) years, and active disease with SLEDAI-2K at baseline 12.0 (8.0-16.0). The frequency of age-associated B cells (ABCs; CD27-IgD-CD11c+ CD21-) decreased by 13% (p=0.03) in the first two to four months after rituximab start, while globally the DN (IgD-CD27-) B cells transiently increased by around 3% (p=0.15) at the first follow-up. This increase could not be attributed to the DN1 (CXCR5+CD11c-) or DN2 (CXCR5-CD11c+) subsets but to the CD11c-CXCR5- DN (DN3) B cells (increase= 6.7%, p=0.03). In parallel, T effector cells (CCR7- CD45RA+) and TEMRA (CD45RA+ CCR7-) frequencies increased after first follow up in both CD4+ and CD8+ T cells. The frequency of TFH (CXCR5+ PD-1+) cells did not change after rituximab, however a decrease of PD-1high CD4+ cells was observed in most patients, although not significant, after 2-4 month of treatment. In most patients the frequency of PD-1high CD4+ cells either reduce or stay the same after RTX treatment (reduction= 0.53, p=0.28). After 11-15 months of RTX treatment the frequency of PD-1high CD4+ T cell reduces by a -0.5% in comparison to 2-4 months (p=0.039). The SLEDAI at baseline did not correlate with the frequency of PD-1high CD4+ T cells (r=0.03, p=0.9).Conclusion:the importance of T cell - B cell interactions in SLE pathogenesis was recently strengthened by the identification of the lymphocyte subsets TFH/TPH and ABCs respectively. Here, in the context of rituximab treated SLE, we could detect a reduction in the frequencies of both ABCs and PD-1high T cells after treatment with rituximab, while the DN3 and effector memory T cells frequencies increased. Our data suggests that anti-CD20 mediated B-cell depletion affects both B-cell and T-cell subsets frequencies, and that monitoring these specific cell subsets may be clinically relevant.References:[1]Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, Wang G, et al. PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI insight. 2019;4(20)Disclosure of Interests:Francesca Faustini Speakers bureau: More than two years ago and not in relation to any aspect of the present research, Natalie Sippl: None declared, Ragnhild Stålesen: None declared, Karine Chemin: None declared, Iva Gunnarsson: None declared, Vivianne Malmström: None declared.

The Role of B and T Lymphocytes in Recurrent Acquired Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3521-3521
Author(s):  
Mariagabriella Mariani ◽  
Andrea Cairo ◽  
Roberta Palla ◽  
Luca Andrea Lotta ◽  
Andrea Rovati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cellular Immunity ◽  
T Cell Subsets ◽  
Surface Markers ◽  
Thrombocytopenic Purpura ◽  
B Cell Subsets

Abstract Abstract 3521 Poster Board III-458 Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by thrombocytopenia, microangiopathic haemolytic anemia and widespread microvascular thrombosis, resulting in multiorgan ischemia. Acquired TTP, which accounts for approximately 95% of cases, can be either associated to anti ADAMTS13 autoantibodies or secondary to a number of associated conditions (tumors, organ transplantation, use of drugs, pregnancy). There are several key questions that remain unanswered, including the importance of cellular immunity in immunomediated TTP, and the search for laboratory markers that predict disease relapse, an event that occurs in 20% to 50% of patients who survive the acute initial episode. Since alterations of peripheral B and T cell subsets in patients with autoimmune diseases (i.e. rheumatoid arthritis and systemic lupus erythematous) are well established, the aim of this study was to analyze the role of B and T cells in acquired TTP and during its recurrence. Methods 36 healthy controls and 36 consecutive patients affected by acquired TTP during remission (defined as the maintenance of normalization of clinical and laboratory data for at least 30 days after the last plasma therapy following the resolution of the last acute episode) were characterized by flow cytometry for the quantification of: - different peripheral B cell subsets, using labeled surface markers anti-CD19-PerCP, anti-IgD-PE, anti-IgM-FITC, anti-CD27-APC, anti-CD38-FITC; - different peripheral T cell subsets, using labeled surface markers anti-CD3-FITC, anti-CD4-PE, anti-CD8-APC, anti-CD25-FITC. For Treg cell quantification (only 17 patients were analyzed), anti-CD3-PerCP, anti-CD4-FITC, anti-CD25-PE and the intracellular marker FoxP3 were used. Patients were classified in two subgroups: those who developed at least two episodes of TTP (n=19, with recurrence) and those who experienced a single episode only and no relapse during at least one year of retrospective observational time (n=17). ADAMTS13 activity was measured by residual collagen binding assay (Gerritsen et al, Thromb Haemost 1999). The presence of anti-ADAMTS13 IgG was evaluated by Western blotting and ELISA assays, using recombinant ADAMTS13 protein as antigen and patients' plasma as a source of antibody. The presence of anti-ADAMTS13 IgA, IgM, IgG subclasses (IgG1, 2, 3, 4) were evaluated by ELISA assays. For continuous variables, differences between controls and patients and between patients with or without recurrence were evaluated by the t-test; for discrete variables, by the chi square test. P values smaller than 0.05 were considered statistically significant. Analyses were performed using the SPSS package version 17.0. Results 1) TTP patients had an increased number of CD19+ B cells (mean ± SD 13% ± 5) compared with the control group (10% ± 3, p=0.001). No difference was observed in T cells subsets. 2) The results of the characterization of the two groups of patients (with and without recurrence) are reported in the table. Patients with and without recurrence did not differ either in the amount of Treg FoxP3 or in the presence of IgA, IgM and IgG subclasses. Discussion The increased B cell numbers in acquired TTP indicates an enhanced activation of cellular immunity. Analysis of B cell subsets, particularly of memory B cells, and of T cells CD24+CD25+ during remission might provide information on the likelihood of recurrence in TTP. In conclusion, in recurrent TTP patients the higher amount of B cells might result in persistent autoantibodies production whilst the decreased level of T cells CD4+CD25+ may lead to a decreased inhibition of autoreactive T cells. These findings may explain the higher level of recurrence in these patients. Disclosures: Peyvandi: Archemix Corporation: Consultancy.

Response to B-cell–depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2924-2930 ◽  
Author(s):  
Roberto Stasi ◽  
Giovanni Del Poeta ◽  
Elisa Stipa ◽  
Maria Laura Evangelista ◽  
Margherita M. Trawinska ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Fas Ligand ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Control Group ◽  
Region Gene ◽  
Thrombocytopenic Purpura

AbstractRituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of different peripheral blood T-cell subsets, the apoptosis profile, as well as the changes of T-cell receptor (TCR) β-variable (VB) region gene usage of CD4+ and CD8+ T-cell subpopulations following rituximab therapy. The study involved 30 patients with chronic ITP who received rituximab, of whom 14 achieved a durable (> 6 months) response. Compared with the control group, pretreatment abnormalities of T cells in ITP patients included an increase of the Th1/Th2 ratio and of the Tc1/Tc2 ratios (P < .001), increased expression of Fas ligand on Th1 and Th2 cells (P < .001), increased expression of Bcl-2 mRNA (P = .003) and decreased expression of bax mRNA (P = .025) in Th cells, and expansion of oligoclonal T cells with no preferential use of any TCR VB subfamily. These abnormalities were reverted in responders at 3 and 6 months after treatment, whereas they remained unchanged in nonresponders. Our findings indicate that in patients with ITP, response to B-cell depletion induced by rituximab is associated with significant changes of the T-cell compartment.

scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

2021 ◽  
Author(s):  
Aline Teixeira ◽  
Alexandria Gillespie ◽  
Alehegne Yirsaw ◽  
Emily Britton ◽  
Janice Telfer ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
Γδ T Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Economic Losses ◽  
Γδ T Cell ◽  
Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

scholarly journals Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavel V. Shelyakin ◽  
Ksenia R. Lupyr ◽  
Evgeny S. Egorov ◽  
Ilya A. Kofiadi ◽  
Dmitriy B. Staroverov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cell Compartments ◽  
Expression Of Genes ◽  
Tcr Repertoire ◽  
Antigen Presenting

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

Therapy of B Cell Malignancies with CD19-Specific Chimeric Antigen Receptor-Modified T Cells of Defined Subset Composition

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 384-384 ◽  
Author(s):  
Cameron J Turtle ◽  
Daniel Sommermeyer ◽  
Carolina Berger ◽  
Michael Hudecek ◽  
David M Shank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Research Funding ◽  
T Cell Subsets ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Abstract BACKGROUND: The adoptive transfer of CD19-specific chimeric antigen receptor-modified (CD19 CAR) T cells is a promising strategy for treating patients with CD19+ B cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). Dramatic responses have been observed in a subset of patients receiving CD19 CAR T cell therapy, and prior studies suggest that persistence of transferred T cells may correlate with the extent of tumor regression. The use of unselected T cells to prepare CAR T cells results in variation in the phenotypic composition of the infused product in individual patients, making it difficult to determine whether particular T cell subsets contribute to efficacy and/or toxicity. Studies in our lab demonstrated that genetically modified effector T cells derived from purified T cell subsets differ in the capacity to persist in vivo after adoptive transfer, and that a combination of CAR-modified CD8+ central memory (TCM) and CD4+ T cells provides optimal antitumor activity in tumor xenograft models. Based on these data, we designed the first clinical trial in which patients with CD19+ B cell malignancies receive CD19 CAR T cells comprised of a defined composition of CD8+ TCM and CD4+T cells engineered to express a CD19 CAR. METHODS: Patients with relapsed or refractory CD19+ ALL, CLL or NHL are eligible for this phase I/II study. CD8+ TCM and CD4+ T cells were separately enriched by immunomagnetic selection from a leukapheresis product from each patient, and cryopreserved. The CD8+ TCM and CD4+ T cells were stimulated in independent cultures with anti-CD3/anti-CD28 paramagnetic beads, and transduced with a lentivirus encoding the murine FMC63 anti-CD19 scFv, 4-1BB and CD3 zeta signaling domains. After in vitro expansion, the cell product for infusion was formulated in a 1:1 ratio of CD4+:CD8+ CAR+ T cells. A truncated non-functional human epidermal growth factor receptor (EGFRt) encoded in the transgene cassette allowed identification of transgene-expressing T cells by flow cytometry. Lymphodepleting chemotherapy was administered followed by infusion of EGFRt+ CAR T cells at one of three dose levels (2 x 105 EGFRt+ cells/kg, 2 x 106 EGFRt+ cells/kg, 2 x 107 EGFRt+cells/kg). RESULTS: Twenty patients with relapsed or refractory ALL (n = 9), NHL (n = 10) or CLL (n = 1), including those who failed prior autologous (n = 4) or allogeneic (n = 4) stem cell transplant have been treated on the trial. Fifteen of 20 treated patients received a product that conformed to the prescribed CD8+ T­CM:CD4 composition. Five patients received a product manufactured using a modified strategy either due to low blood lymphocyte counts (n = 3) or due to failure to propagate T cells in culture (n = 2). CD8+ TCM and CD4+ T cells have been isolated from 12 additional patients and cryopreserved for therapy. Patients have been treated at all three dose levels without acute infusional toxicity. Severe cytokine release syndrome (sCRS) consisting of fever, hypotension, and reversible neurotoxicity associated with elevated serum IFN-γ and IL-6 was only observed in ALL patients with a high tumor burden. One ALL patient treated at the highest cell dose died of complications associated with sCRS. None of the NHL patients had sCRS. Of patients who are >6 weeks after CD19 CAR T cell therapy, best responses included complete (n=1) or partial (n=5) remission in 6/9 patients with NHL and complete remission in 5/7 patients with ALL. Both CD4+ and CD8+ CAR-T cells expanded in vivo and could be detected in blood, marrow and CSF. The peak level and duration of persistence of both CD4+ and CD8+ EGFRt+ T cells were associated with clinical response. TCRBV gene sequencing of flow sorted CD4+ and CD8+ EGFRt+CAR T cells from 2 patients showed that proliferating CAR T cells were polyclonal. A subset of NHL patients in whom CAR T cells became undetectable developed a T cell immune response to sequences in the murine CD19-specific scFv component of the CAR transgene. CONCLUSION: Adoptive immunotherapy with CD19 CAR T cells of defined subset composition is feasible and safe in a majority of heavily pretreated patients with refractory B cell malignancies and has potent anti-tumor activity. Persistence of CAR-T cells may be limited in some patients by transgene product immunogenicity. Data from this ongoing clinical trial will be updated at the meeting. Disclosures Turtle: Juno Therapeutics: Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Hudecek:Juno Therapeutics: Patents & Royalties. Jensen:Juno: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Riddell:Juno Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Maloney:Juno Therapeutics: Research Funding.

scholarly journals In Situ Activation of Helper T Cells in the Lung

2001 ◽  
Vol 69 (8) ◽  
pp. 4790-4798 ◽  
Author(s):  
Bindu Raju ◽  
Chung F. Tung ◽  
Debbie Cheng ◽  
Nora Yousefzadeh ◽  
Rany Condos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Helper T Cells ◽  
Cell Marker ◽  
Color Flow ◽  
Purified Protein Derivative ◽  
Surface Molecules ◽  
In Situ Activation ◽  
Significant Difference

ABSTRACT To better understand the lung and systemic responses of helper T cells mediating memory immunity to Mycobacterium tuberculosis, we used three- and four-color flow cytometry to study the surface phenotype of CD4+ lymphocytes. Bronchoalveolar lavage (BAL) fluid and peripheral blood (PB) samples were obtained from a total of 25 subjects, including 10 tuberculosis (TB)-infected subjects, 8 purified-protein-derivative-negative subjects, and 7 purified-protein-derivative-positive subjects. In marked contrast to CD4+ lymphocytes from PB (9% ± 5% expressing CD45RA and CD29), the majority (55% ± 16%) of CD4+ lymphocytes in BAL (ALs) simultaneously expressed CD45RA, a naı̈ve T-cell marker, and CD29, members of the very late activation family. Further evaluation revealed that CD4+ ALs expressed both CD45RA and CD45RO, a memory T-cell marker. In addition, the proportion of CD4+ lymphocytes expressing CD69, an early activation marker, was drastically increased in BAL fluid (83% ± 9%) compared to PB (1% ± 1%), whereas no significant difference was seen in the expression of CD25, the low-affinity interleukin 2 receptor (34% ± 15% versus 40% ± 16%). More importantly, we identified a minor population of CD69bright CD25bright CD4+lymphocytes in BAL (10% ± 6%) that were consistently absent from PB (1% ± 1%). Thus, CD4+ lymphocytes in the lung paradoxically coexpress surface molecules characteristic of naı̈ve and memory helper T cells as well as surface molecules commonly associated with early and late stages of activation. No difference was observed for ALs obtained from TB-infected and uninfected lung segments in this regard. It remains to be determined if these surface molecules are induced by the alveolar environment or if CD4+ lymphocytes coexpressing this unusual combination of surface molecules are selectively recruited from the circulation. Our data suggest that ex vivo experiments on helper T-cell subsets that display distinctive phenotypes may be pivotal to studies on the human immune response to potential TB vaccines.

scholarly journals Flow Cytometric Analysis Revealed a Significant Accumulation of Terminally Differentiated T cell Subtypes in the Circulating Lymphocytes of Cytomegalovirus (CMV) Positive Follicular Lymphoma Patients

2021 ◽  
pp. 1-9
Author(s):  
Lugos MD ◽  
◽  
Dangana A ◽  
Ntuhun BD ◽  
Oluwatayo BO ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Flow Cytometric Analysis ◽  
B Cell Lymphoma ◽  
T Cell Subsets ◽  
Cmv Infection ◽  
Flow Cytometric ◽  
The Impact

Follicular lymphoma (FL), a non-Hodgkin lymphoma, is an indolent cancer of the B cell lineage that runs a chronic deterioration course that can result in multiple treatment episodes leading to resistance and possible transformation to diffuse large B cell lymphoma. Cytomegalovirus (CMV) reactivation during chemotherapy or after an organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality. This study tests the hypothesis that some of the heterogeneity of FL might result from chronic infection with Cytomegalovirus (CMV). This research was intended to appraise the impact of CMV infection on the subtypes of T cells in follicular lymphoma patients. We accessed stored peripheral blood mononuclear cells (PMBCs) from patients of known CMV serostatus recruited into an FL clinical trial. We undertook a multicolour flow cytometric analysis of the PBMCs and compared the number of lymphocyte subtypes of CMV-positive and CMV-negative FL patients. Data showed a significant increase in the quantity of terminally differentiated (TEMRA) T cell subsets, including EM3-CD8 (P=0.005), EM3-CD4 (P=0.018), E-CD4 (P=0.029), E-CD8 (P=0.033) and pE2-CD4 (P=0.046) phenotypes, as well as increased NKT cells (P=0.031) among CMV-positive patients compared to the negative group. Our findings support the hypothesis that recurrent infections characterise CMV infection in FL due to accelerated immune senescence and the accumulation of exhausted T cells. Based on the data, a case could be argued for the routine application of CMV screening in FL before treatment with chemo-immunotherapy to implement enhanced infection surveillance in CMV-positive patients. These discoveries can eventually help improve the treatment approaches in the management of FL toward a combinatorial viewpoint for direct cytotoxic and indirect immunomodulatory outlook

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