scholarly journals SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency

2021 ◽  
pp. 1-15
Author(s):  
Sudhir Gupta ◽  
Houfen Su ◽  
Tejal Narsai ◽  
Sudhanshu Agrawal
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immunocompetent Patient ◽  
T Cell Response ◽  
Effector Memory ◽  
Cvid Patient ◽  
Marginal Zone B Cells ◽  
Immunological Responses ◽  
Humoral Immunodeficiency ◽  
B Cell Subsets

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (T<sub>N</sub>), central memory (T<sub>CM</sub>), effector memory (T<sub>EM</sub>), and terminally differentiated effector memory (T<sub>EMRA</sub>) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cT<sub>FH</sub>, T<sub>FH</sub>1, T<sub>FH</sub>2, T<sub>FH</sub>17, T<sub>FH</sub>1/T<sub>FH</sub>17, and T<sub>FR</sub>), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21<sup>low</sup> B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.

scholarly journals Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS

2021 ◽  
Vol 8 (2) ◽  
pp. e940
Author(s):  
José I. Fernández-Velasco ◽  
Jens Kuhle ◽  
Enric Monreal ◽  
Virginia Meca-Lallana ◽  
José Meca-Lallana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Response ◽  
Effector Memory ◽  
Neurofilament Light Chain ◽  
Necrosis Factor Alpha ◽  
Primary Progressive ◽  
Gm Csf ◽  
Bonferroni Test

ObjectiveTo analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS).MethodsIn this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test.ResultsOcrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd− patients with baseline sNfL >10 pg/mL.ConclusionsIn PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point

2007 ◽  
Vol 81 (11) ◽  
pp. 5759-5765 ◽  
Author(s):  
John W. Northfield ◽  
Christopher P. Loo ◽  
Jason D. Barbour ◽  
Gerald Spotts ◽  
Frederick M. Hecht ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Absolute Number ◽  
T Cell Response ◽  
Effector Memory ◽  
Set Point ◽  
Effector Memory T Cells ◽  
Viral Load Set Point ◽  
Hiv 1

ABSTRACT CD8+ T cells are believed to play an important role in the control of human immunodeficiency virus type 1 (HIV-1) infection. However, despite intensive efforts, it has not been possible to consistently link the overall magnitude of the CD8+ T-cell response with control of HIV-1. Here, we have investigated the association of different CD8+ memory T-cell subsets responding to HIV-1 in early infection with future control of HIV-1 viremia. Our results demonstrate that both a larger proportion and an absolute number of HIV-1-specific CD8+ CCR7− CD45RA+ effector memory T cells (TEMRA cells) were associated with a lower future viral load set point. In contrast, a larger absolute number of HIV-1-specific CD8+ CCR7− CD45RA− effector memory T cells (TEM) was not related to the viral load set point. Overall, the findings suggest that CD8+ TEMRA cells have superior antiviral activity and indicate that both qualitative and quantitative aspects of the CD8+ T-cell response need to be considered when defining the characteristics of protective immunity to HIV-1.

scholarly journals Sialoadhesin-Deficient Mice Exhibit Subtle Changes in B- and T-Cell Populations and Reduced Immunoglobulin M Levels

2006 ◽  
Vol 26 (4) ◽  
pp. 1549-1557 ◽  
Author(s):  
Cornelia Oetke ◽  
Mary C. Vinson ◽  
Claire Jones ◽  
Paul R. Crocker
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immunoglobulin M ◽  
Cell Populations ◽  
Lymphoid Tissues ◽  
Marginal Zone B Cells ◽  
Developmental Abnormalities ◽  
Inflammatory Macrophages ◽  
T Cell Maturation ◽  
Deficient Mice

ABSTRACT Sialoadhesin (Sn, also called Siglec-1 or CD169) is a transmembrane receptor and the prototypic member of the Siglec family of sialic acid binding immunoglobulin-like lectins. It is expressed on specialized subsets of resident macrophages in hematopoietic and lymphoid tissues and on inflammatory macrophages. In order to investigate its function, we generated Sn-deficient mice and confirmed that these mice are true nulls by fluorescence-activated cell sorter analysis and immunohistochemistry. Mice deficient in Sn were viable and fertile and showed no developmental abnormalities. Analysis of cell populations revealed no differences in bone marrow, peritoneal cavity, and thymus, but there was a small increase in CD8 T cells and a decrease in B220-positive cells in spleens and lymph nodes of Sn-deficient mice. Furthermore, in spleen there was a slight decrease in follicular B cells with an increase in numbers of marginal zone B cells. B- and T-cell maturation as well as responses to stimulation with thioglycolate were only slightly affected by Sn deficiency. Immunoglobulin titers in Sn-deficient mice were significantly decreased for immunoglobulin M (IgM) but similar for IgG subclasses. These results suggest a role for sialoadhesin in regulating cells of the immune system rather than in influencing steady-state hematopoiesis.

scholarly journals Immune Response to SARS-CoV-2 Vaccine in 2 Men

2021 ◽  
pp. 1-10
Author(s):  
Sudhir Gupta ◽  
Houfen Su ◽  
Sudhanshu Agrawal
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Specific Response ◽  
Igg Antibodies ◽  
Marginal Zone B Cells ◽  
Transitional B Cells ◽  
T Subsets ◽  
B Cell Subsets ◽  
Regulatory Lymphocytes

<b><i>Introduction:</i></b> In the trials of corona virus vaccines, detailed analyses of subsets of lymphocytes were not carried out. We present perhaps the most comprehensive immunological analysis of 29 subsets of B and T cells in 2 healthy subjects receiving 2 doses of the Pfizer SARS-CoV-2 (COVID-19) vaccine. <b><i>Methods:</i></b> Analyses were performed prior to vaccination, 3 weeks following the 1st dose, and 4 weeks following the 2nd dose. Total, naïve (T<sub>N</sub>), and different memory and effector subsets (T<sub>CM</sub>, T<sub>EM</sub>, and T<sub>EMRA</sub>) of CD4+ and CD8+ T cells; SARS-CoV-2 spike protein-specific tetramer+, and cytotoxic CD8+ T; subsets of T follicular cells (T<sub>FH</sub>, T<sub>FH</sub>1, T<sub>FH</sub>2, T<sub>FH</sub>1/T<sub>FH</sub>17, and T<sub>FH</sub>17); B-cell subsets (mature B cells, naive B cells, transitional B cells, marginal zone B cells, class-switched memory B cells, germinal center B cells, and CD21<sup>low</sup> B cells), and plasmablasts; and regulatory lymphocytes (CD4+ Treg, CD8+ Treg, Breg, and T<sub>FR</sub> cells) were evaluated with specific monoclonal antibodies by flow cytometry. <b><i>Results:</i></b> A lack of COVID-19 IgG antibodies after the 1st dose in one of 2 subjects was associated with increased regulatory lymphocytes and decreased plasmablasts. Seroconversion after the 2nd dose in this subject was associated with decreased T<sub>FR</sub> cells and increased plasmablasts. In both subjects, CD4 T<sub>EM</sub> and CD8 T<sub>CM</sub> were markedly increased following the 2nd dose. T<sub>FH</sub>1 and regulatory lymphocytes were increased (except Breg) following the 1st dose. A striking increase in SARS-CoV-2-specific CD8+ T cells was observed following the 2nd dose. <b><i>Conclusion:</i></b> Our data support the need for 2nd dose of vaccine to induce strong SARS-CoV-2 CD8 T-cell specific response and generation of memory subsets of CD4+ and CD8+ T cells. Regulatory lymphocytes appear to play a role in the magnitude of response.

scholarly journals Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

2021 ◽  
Author(s):  
Antonella Scaglione ◽  
Silvana Opp ◽  
Alicia Hurtado ◽  
Christine Pampeno ◽  
Ziyan Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
T Cell Response ◽  
Spike Protein ◽  
Effector Memory ◽  
World Population ◽  
Vaccine Platform ◽  
Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

scholarly journals High-Dimensional Immunophenotyping of Murine T-cell and B-cell Subsets

2020 ◽  
Author(s):  
Kyle T. Mincham ◽  
Jacob D. Young ◽  
Deborah H. Strickland
Keyword(s):  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Effector Memory ◽  
High Dimensional ◽  
Cell Populations ◽  
Lymphoid Tissues ◽  
Murine Models ◽  
Follicular Helper ◽  
B Cell Subsets

Purpose and appropriate sample typesThis 19-parameter, 18-colour flow cytometry panel was designed and optimised to enable the comprehensive and simultaneous immunophenotyping of distinct T-cell and B-cell subsets within murine lymphoid tissues (Table 1). Cellular populations identified by employing this OMIP include 4 major subsets of B-cells (memory, activated, plasma cells and plasmablasts) and 7 major subsets of CD4+ T-cells (naïve, central memory, effector memory, helper, regulatory, follicular helper and follicular regulatory). Staining was performed on freshly isolated splenocytes from 21-day-old neonatal BALB/c mice, however due to the omission of mouse strain-specific markers, this OMIP can be implemented across a range of murine models where in-depth immunophenotyping of the diverse repertoire of T-cell and B-cell populations localised within lymphoid tissues is required.

scholarly journals The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

2016 ◽  
Vol 213 (10) ◽  
pp. 2167-2185 ◽  
Author(s):  
Alejo Chorny ◽  
Sandra Casas-Recasens ◽  
Jordi Sintes ◽  
Meimei Shan ◽  
Nadia Polentarutti ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
T Cell ◽  
B Cells ◽  
Marginal Zone ◽  
Fluid Phase ◽  
Pattern Recognition Receptor ◽  
Marginal Zone B Cells ◽  
Adaptive Immune ◽  
Recognition Receptor

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation–related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell–independent and T cell–dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.

scholarly journals Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

2013 ◽  
Vol 81 (11) ◽  
pp. 4171-4181 ◽  
Author(s):  
Laura A. Cooney ◽  
Megha Gupta ◽  
Sunil Thomas ◽  
Sebastian Mikolajczak ◽  
Kimberly Y. Choi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Parasite Development ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

Marginal Zone B Cells Mediate a CD4 T Cell Dependent Extrafollicular Antibody Response Following RBC Transfusion in Mice

Blood ◽  
2021 ◽  
Author(s):  
Patricia E Zerra ◽  
Seema R Patel ◽  
Ryan Philip Jajosky ◽  
Connie M Arthur ◽  
James W McCoy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
T Cell Activation ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Marginal Zone B Cells ◽  
Rbc Transfusion

Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme and ovalbumin fused to human Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they co-localize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited IgM and IgG anti-HOD antibody formation, while CD4 T cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild type or MZ B cell deficient recipients, suggesting that IgG formation is not dependent on MZ B cell-mediated CD4 T cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response and no increase in antigen specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

scholarly journals Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001157
Author(s):  
Juliane Schuhmacher ◽  
Sonja Heidu ◽  
Torben Balchen ◽  
Jennifer Rebecca Richardson ◽  
Camilla Schmeltz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Cell Response ◽  
Small Gtpase ◽  
T Cell Response ◽  
Effector Memory ◽  
Tolerability Profile

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

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