Role of Adaptive Regulatory T Cells in the Induction of Tolerance to FVIII

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1027-1027 ◽  
Author(s):  
Jonathan Skupsky ◽  
Elika Farrokhi ◽  
David W. Scott
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
B Cell ◽  
Fluorescent Protein ◽  
Tolerance Induction ◽  
Coagulation Factor

Abstract Individuals who lack a given protein may never properly develop self tolerance. Thus, the administration of protein therapeutics can lead to undesirable immune responses. A classic example is that patients with Hemophilia A can develop an inhibitory immune response to therapeutic treatments with coagulation factor VIII (fVIII). Several years ago, we developed a B-cell delivered gene therapy based approach to prevent this response and a mouse model to study the mechanisms of the induction and maintenance of immunological tolerance to fVIII inhibitors. This model takes advantage of a knock-in mouse with the transcription factor, FoxP3, in frame with green fluorescent protein (GFP). FoxP3 is considered to be a marker for regulatory T cells (Tregs). The FoxP3-GFP knock-in allows us to follow existing (natural) Tregs and the induction of adaptive Tregs. We have backcrossed this mouse, which expresses GFP in all FoxP3+ Tregs, with the hemophilic mouse, which has an existing deletion in fVIII (E16), for 10 generations. Establishing a mouse that is transgenic for both the FoxP3-GFP fusion and a deletion in fVIII will enhance future clinically oriented experiments to understand how tolerogenic B cells interact with Tregs in a hemophilia system. Lymphocytes from these mice have now been characterized using flow cytometry and confocal microscopy, and analyzed during treatment with tolerogenic B cells. These cells express Treg markers that include, CD25, CTLA-4, GITR and reduced amounts of CD127. However, the population of fVIII antigen-specific cells is small in this mouse model. Thus, it is difficult to detect changes over the natural variation found between mice in a colony, although small changes have been detected. To explore the underlying role of Tregs in tolerance induction, we have bred an ovalbumin (OVA)-specific, T-cell receptor (TCR) transgenic mouse that contains the FoxP3-GFP fusion (FoxP3GFP/DO11.10 and FoxP3GFP/DO11.10/Rag2−/−). Using our B-cell delivered tolerance protocol, we can prevent immunization when an immunologically competent mouse is immunized with OVA in adjuvant. When FoxP3GFP/DO11.10 TCR transgenic mice are treated with OVA-Ig transduced B cells, we found a significant increase in antigen-specific Tregs (p<0.05). Finally, when the same treatment is performed on FoxP3GFP/DO11.10/Rag2−/−, which completely lack natural regulatory cells, we found that FoxP3 was expressed in 4% (p<0.001) of T-cells above background. These cells express markers typical of Tregs. These data strongly support the hypothesis that transduced B cell treatment induces a regulatory phenotype in the antigen-specific T cell population. To extend this system to the hemophilia model, fVIII C2 tetramers will be used to label and isolate antigen-specific T cells during tolerance induction. Additionally, this model opens up avenues of analysis to intra-vital microscopy which gives a true representation of interactions in a live organism. (Supported by NIH RO1 HL061883, NIH T32 HL007698, and a predoctoral fellowship from the American Heart Association.)

Conditioning Intensity and T Cell Dose Determine Efficacy of CD19-Targeted T Cell-Mediated Tumor Eradication in an Immunocompetent Mouse Model of B-ALL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2613-2613
Author(s):  
Marco L Davila ◽  
Christopher Kloss ◽  
Renier J Brentjens ◽  
Michel Sadelain
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immunocompetent Mouse ◽  
Cell Dose ◽  
Conditioning Intensity

Abstract Abstract 2613 Recent work by our group and others demonstrates the therapeutic potential of CD19-targeted T cells to treat patients with indolent B cell malignancies. These studies make use of T cells that are genetically engineered with chimeric antigen receptors (CARs) comprising an scFv fused to various T cell activating elements. Whereas firs-generation CARs only direct T cell activation, second-generation CARs include two signal elements, such as CD3z and CD28 signaling domains (19–28z). We and our colleagues at MSKCC are currently evaluating the safety of 19–28z-transduced T cells in patients with acute leukemia (B-ALL) in a Phase I protocol (NCT01044069). Pre-clinical studies performed to date have mostly relied on xenogeneic models utilizing immunodeficient animals, which enable the evaluation of human engineered T cells but do not recapitulate all the interactions that may affect tumor eradication by CAR-modified T cells. We have therefore developed a pre-clinical immunocompetent mouse model of B-ALL, and addressed therein the impact of conditioning and T cell dose on the eradication of leukemia by syngeneic, CAR-targeted T cells. To establish an immunocompetent mouse model of B cell leukemia, we generated a clone from the lymph node of an Eμ-myc B6 transgenic mouse. The immunophenotype and gene-expression profile of clone Eμ-ALL01 is consistent with a progenitor B cell origin. Syngeneic B6 mice inoculated with this clone develop florid acute leukemia and die approximately 2–4 weeks after injection from progressive bone marrow infiltration. We created an anti-mouse CD19 CAR comprising all murine elements, including the CD8 signal peptide, a CD19-specific single chain variable fragment, the CD8 transmembrane region, and the CD28 and CD3z signaling domains. Transduction of the murine 19–28z CAR into mouse T cells was robust and successfully retargeted the T cells to B cells. In vitro assays demonstrated that m19–28 z transduced T cells mediated effective killing of CD19-expressing target cells and the production of effector cytokines such as IFNγ and TNFα. Cyclophosphamide either alone or in combination with control syngeneic T cells is insufficient to eradicate established Eμ-ALL01 in B6 mice. However, treatment with cyclophosphamide and m19–28z-transduced T cells cured nearly all mice. Mice sacrificed six months after treatment exhibited a dramatic reduction of B cells in the bone marrow (BM), blood, and spleen. The few remaining B lineage cells found in the BM had a phenotype consistent with early pro-B cells, suggesting that endogenous reconstitution of the B cell compartment was thwarted by persisting, functional m19–28z+ T cells. Thus, T cells are retained at the site of antigen expression, which is maintained through regeneration of progenitor B cells. The persisting CD19-targeted T cells in the BM exhibited a cell surface phenotype consistent with effector and central memory cells. Using B cell aplasia as a surrogate endpoint for assessing in vivo T cell function and persistence, we evaluated how conditioning chemotherapy and T cell dose determine the level of B cell depletion induced by adoptively transferred CD19-targeted T cells. Overall, increasing the cyclophosphamide or T cell dose, increased the degree and duration of B cell depletion and the number of persisting CAR-modified T cells. Significantly, increasing the T cell dose at a set cyclophosphamide level had a lesser impact than increasing the conditioning intensity for a given T cell dose. In summary, the new Eμ-ALL01 syngeneic, immunocompetent B-ALL model we describe here is a valuable tool for modeling CD19 CAR therapies. Our results indicate that m19–28z transduced T cells are effective at eradicating B-ALL tumor cells and persist long-term, preferentially in bone marrow. Our findings further establish that conditioning intensity and T cell dose directly determine B cell elimination and long-term T cell persistence. These studies in mice will serve as an important framework to further model and perfect our studies in patients with B-ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice

2018 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Alexis Saintamand ◽  
Amandine David ◽  
Mehdi Alizadeh ◽  
François Boyer ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immune Suppression ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma

AbstractTransformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.Summary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

scholarly journals Tertiary Lymphoid Structure-B Cells Narrow Regulatory T Cells Impact in Lung Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Claire Germain ◽  
Priyanka Devi-Marulkar ◽  
Samantha Knockaert ◽  
Jérôme Biton ◽  
Hélène Kaplon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Lung Cancer Patients ◽  
Lymphoid Structures ◽  
Immune Related Genes ◽  
Nsclc Patients

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment is associated with better clinical outcome in many cancers. In non-small cell lung cancer (NSCLC), we have previously showed that a high density of B cells within TLS (TLS-B cells) is positively correlated with tumor antigen-specific antibody responses and increased intratumor CD4+ T cell clonality. Here, we investigated the relationship between the presence of TLS-B cells and CD4+ T cell profile in NSCLC patients. The expression of immune-related genes and proteins on B cells and CD4+ T cells was analyzed according to their relationship to TLS-B density in a prospective cohort of 56 NSCLC patients. We observed that tumor-infiltrating T cells showed marked differences according to TLS-B cell presence, with higher percentages of naïve, central-memory, and activated CD4+ T cells and lower percentages of both immune checkpoint (ICP)-expressing CD4+ T cells and regulatory T cells (Tregs) in the TLS-Bhigh tumors. A retrospective study of 538 untreated NSCLC patients showed that high TLS-B cell density was even able to counterbalance the deleterious impact of high Treg density on patient survival, and that TLS-Bhigh Treglow patients had the best clinical outcomes. Overall, the correlation between the density of TLS-Bhigh tumors with early differentiated, activated and non-regulatory CD4+ T cell cells suggest that B cells may play a central role in determining protective T cell responses in NSCLC patients.

Non-Hodgkin Lymphoma B-Cells Induce Intratumoral CD4+CD25− T Cells To Express Foxp3 and Gain Regulatory Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1724-1724
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Foxp3 Expression ◽  
Regulatory Function ◽  
Cell Contact ◽  
Cancer Pathogenesis

Abstract We have previously shown that CD4+CD25+Foxp3+ regulatory T cells from NHL tumors suppress the function of infiltrating CD4+ T cells and cytolytic CD8+ T cells. Expression of Foxp3 has been demonstrated to be crucial to the development and function of CD4+CD25+ regulatory T cells. However, the mechanistic details that drive development of Foxp3 expression in T cells, in both the normal and malignant scenario, remains to be fully elucidated. Previous studies suggest that Foxp3 expression in CD4+CD25− T cells can be upregulated by tolerizing stimuli such as activation through TCR, corticosteroids, estrogen, and TGF-beta. Because lymphoma B cells have been shown to induce T-cell tolerance, we postulated that lymphoma B cells may play a role in the generation of regulatory T cells by inducing Foxp3 expression in CD4+CD25− T cells. FoxP3 expression was initially thought to be restricted to CD4+CD25+ regulatory T cell population. However, recent literature suggests that Foxp3 may also be expressed in CD4+CD25− T cells. Using biopsy specimens from patients with B-cell NHL, we found that a subset, 15%, of infiltrating CD4+CD25− T cells express Foxp3 and are capable of suppressing the proliferation and granule production of infiltrating cytotoxic CD8+ T cells. These initial studies suggest that CD4+CD25−Foxp3+ T cells have regulatory function. To explore the underlying mechanism by which Foxp3 expression is regulated, we determined the effect of costimulatory signals on Foxp3 expression in CD4+CD25−Foxp3− T cells. Activation with OKT3/anti-CD28 Ab as well as DC-mediated activation induced Foxp3 expression in a subset of CD4+CD25− T cells. We also found that the presence of lymphoma B cells during activation augmented the induction of Foxp3 expression in CD4+CD25− T cells and that NHL B cell-mediated Foxp3 expression was cell contact-dependent. To better understand the contribution of NHL B cells in Foxp3 expression, we explored the possibility that CD27-CD70 interaction may be involved in Foxp3 expression. Lymphoma B cells express CD70, but not B7-1 and B7-2, which have been shown to be important in protecting tumor cells from lysis and contributing to cancer pathogenesis. Ligation of CD27 by receptor cross-linking enhanced Foxp3 expression in infiltrating CD4+CD25− T cells in B-cell NHL. Taken together these studies reveal a novel role for NHL B cells in development of regulatory T cells. Our data show that lymphoma B cells induce expression of Foxp3 in infiltrating CD4+CD25− T cells and may result in development of T cells with regulatory function within the tumor microenvironment. Our results also suggest a potential role for CD27-CD70 interactions in this process. The ability of malignant B cells to drive development of regulatory T cells may be one mechanism by which lymphoma B cells protect themselves from anti-tumor immunity. (Supported in part by the Iowa/Mayo Lymphoma SPORE CA97274).

scholarly journals Effects of Friend Virus Infection and Regulatory T Cells on the Antigen Presentation Function of B Cells

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tyler C. Moore ◽  
Ronald J. Messer ◽  
Lorena M. Gonzaga ◽  
Jennifer M. Mather ◽  
Aaron B. Carmody ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Activation ◽  
T Cell Responses ◽  
B Cell Activation ◽  
Friend Virus ◽  
Cell Responses

ABSTRACTFriend virus (FV) is a naturally occurring mouse retrovirus that infects dividing cells of the hematopoietic lineage, including antigen-presenting cells (APCs). The infection of APCs by viruses often induces their dysfunction, and it has been shown that FV infection reduces the ability of dendritic cells (DCs) to prime critical CD8+T cell responses. Nonetheless, mice mount vigorous CD8+T cell responses, so we investigated whether B cells might serve as alternative APCs during FV infection. Directex vivoanalysis of B cells from FV-infected mice revealed that infected but not uninfected B cells upregulated expression of the costimulatory molecules CD80, CD86, and CD40, as well as major histocompatibility complex class II (MHC-II) molecules. Furthermore,in vitrostudies showed that, compared to uninfected B cells from the same mice, the FV-infected B cells had significantly enhanced APC function, as measured by their capacity to prime CD8+T cell activation and proliferation. Thus, in contrast to DCs, infection of B cells with FV enhanced their APC capacity and ability to stimulate the CD8+T cell responses essential for virus control. FV infections also induce the activation and expansion of regulatory T cells (Tregs), so it was of interest to determine the impact of Tregs on B cell activation. The upregulation of costimulatory molecule expression and APC function of B cells was even more strongly enhanced byin vivodepletion of regulatory T cells than infection. Thus, Tregs exert potent homeostatic suppression of B cell activation that is partially overcome by FV infection.IMPORTANCEThe primary role of B cells in immunity is considered the production of pathogen-specific antibodies, but another, less-well-studied, function of B cells is to present foreign antigens to T cells to stimulate their activation and proliferation. Dendritic cells (DCs) are considered the most important antigen-presenting cells (APCs) for CD8+T cells, but DCs lose APC function when infected with Friend virus (FV), a model retrovirus of mice. Interestingly, B cells were better able to stimulate CD8+T cell responses when they were infected with FV. We also found that the activation status of B cells under homeostatic conditions was potently modulated by regulatory T cells. This study illustrates an important link between B cell and T cell responses and illustrates an additional mechanism by which regulatory T cells suppress critical T cell responses during viral infections.

scholarly journals Marginal Zone B Cells Regulate RBC Alloimmunization Toward Distinct RBC Alloantigens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3847-3847
Author(s):  
Patricia E. Zerra ◽  
Seema R. Patel ◽  
Connie M. Arthur ◽  
Kathryn R. Girard-Pierce ◽  
Ashley Bennett ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Rbc Transfusion

Abstract Background: While red blood cell (RBC) transfusion can be beneficial, exposure to allogeneic RBCs can result in the development of RBC alloantibodies that can make it difficult to obtain compatible RBCs for future transfusions. Aside from phenotype matching protocols, no strategy currently exists that is capable of preventing RBC alloimmunization following therapeutic transfusion. As RBC alloantigens represent diverse determinants capable of driving distinct immune pathways, common immunological nodes must be identified in order to successfully prevent RBC alloimmunization against a variety of different alloantigens. Recent results demonstrate that marginal zone (MZ) B cells mediate anti-KEL antibody formation in the complete absence of CD4 T cells. However, whether MZ B cells similarly regulate RBC alloantibody formation against other RBC alloantigens remains unknown. As a result, we examined the role of MZ B cells and CD4 T cells in the development of RBC alloantibodies following exposure to the HOD (hen egg lysozyme, ovalbumin and duffy) antigen. Methods: Each recipient was transfused with HOD or KEL RBCs following either MZ B cell or CD4 T cell depletion using a cocktail of MZ B cell (anti-CD11a and anti-CD49d) or anti-CD4 depleting antibody, 4 and 2 days prior to transfusion. Control groups received isotype control injections in parallel. MZ B cell deficient (CD19cre/+ X Notch2flx/flx) and CD4 T cell deficient (MHC class II knockout) recipients were also used to examine the role of MZ B cells and CD4 T cells, respectively. Serum collected on days 5 and 14 post-transfusion was evaluated for anti-HOD or anti-KEL antibodies by incubating HOD or KEL RBCs with serum, followed by detection of bound antibodies using anti-IgM and anti-IgG and subsequent flow cytometric analysis. Evaluation of antibody engagement and overall survival of HOD or KEL RBCs was accomplished by labeling RBCs with the lipophilic dye, DiI, prior to transfusion, followed by examination for bound antibody and RBC clearance on days 5 and 14 post-transfusion by flow cytometry. Results: Similar to the ability of MZ B cell depletion to reduce anti-KEL antibody formation following KEL RBC exposure, depletion of MZ B cells significantly reduced anti-HOD IgM and IgG antibodies following HOD RBC transfusion. In contrast, injection of recipients with isotype control antibodies in parallel failed to prevent alloantibody formation following HOD or KEL RBC transfusion. Similar results were obtained following HOD or KEL RBC transfusion into recipients genetically deficient in MZ B cells. In contrast, although MZ B cells were required for HOD and KEL RBC-alloantibody formation, manipulation of CD4 T cells differentially impacted the ability of each antigen to induce alloantibodies. While transfusion of HOD or KEL RBCs resulted in robust IgM alloantibodies in the absence of CD4 T cells, depletion or genetic elimination of CD4 T cells significantly inhibited anti-HOD IgG antibody formation, while failing to impact IgG anti-KEL antibody formation. Consistent with this, while manipulation of CD4 T cells protected HOD RBCs from antibody deposition and subsequent RBC clearance, this same approach failed to similarly protect KEL RBCs following transfusion. In contrast, depletion of MZ B cells not only prevented detectable alloantibody production, but also completely protected HOD or KEL RBCs from antibody deposition and subsequent RBC clearance. Conclusion: These results suggest that while MZ B cells mediate a robust IgM antibody response following either KEL or HOD antigen exposure, MZ B cells appear to possess the capacity to orchestrate unique downstream IgG responses through CD4 T cell dependent and independent pathways contingent on target alloantigen. As a result, while manipulation of CD4 T cells may prevent alloantibody formation against some antigens, targeting this immune population inadequately prevents RBC alloantibody formation against all RBC antigens. As chronic transfusion therapy exposes recipients to a wide variety of alloantigens, these results suggest that MZ B cells may represent a central initiating node that governs RBC alloimmunization against a variety of RBC alloantigens, and may therefore serve as a useful target in preventing alloantibody formation in chronically transfused individuals. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bronchoalveolar Lavage Fluid Reflects a TH1-CD21low B-Cell Interaction in CVID-Related Interstitial Lung Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
David Friedmann ◽  
Susanne Unger ◽  
Baerbel Keller ◽  
Mirzokhid Rakhmanov ◽  
Sigune Goldacker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Interstitial Lung Disease ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
B Cell ◽  
Cell Subset ◽  
Immune Dysregulation

BackgroundAbout 20% of patients with common variable immunodeficiency (CVID) suffer from interstitial lung disease (ILD) as part of a systemic immune dysregulation. Current understanding suggests a role of B cells in the pathogenesis based on histology and increased levels of BAFF and IgM associated with active disease corroborated by several reports which demonstrate the successful use of rituximab in CVID-ILD. It is debated whether histological confirmation by biopsy or even video-assisted thoracoscopy is required and currently not investigated whether less invasive methods like a bronchoalveolar lavage (BAL) might provide an informative diagnostic tool.ObjectiveTo gain insight into potential immune mechanisms underlying granulomatous and lymphocytic interstitial lung disease (GLILD) and to define biomarkers for progressive ILD by characterizing the phenotype of B- and T-cell populations and cytokine profiles in BAL fluid (BALF) of CVID-ILD compared to sarcoidosis patients and healthy donors (HD).MethodsSixty-four CVID, six sarcoidosis, and 25 HD BALF samples were analyzed by flow cytometric profiling of B- and T-cells and for cytokines by ELISA and Multiplexing LASER Bead technology.ResultsBoth sarcoidosis and CVID-ILD are characterized by a predominantly T-cell mediated lymphocytosis in the BALF. There is an increase in T follicular helper (TFH)-like memory and decrease of regulatory T cells in CVID-ILD BALF. This TFH-like cell subset is clearly skewed toward TH1 cells in CVID-ILD. In contrast to sarcoidosis, CVID-ILD BALF contains a higher percentage of B cells comprising mostly CD21low B cells, but less class-switched memory B cells. BALF analysis showed increased levels of APRIL, CXCL10, and IL-17.ConclusionUnlike in sarcoidosis, B cells are expanded in BALF of CVID-ILD patients. This is associated with an expansion of TFH- and TPH-like cells and an increase in APRIL potentially supporting B-cell survival and differentiation and proinflammatory cytokines reflecting not only the previously described TH1 profile seen in CVID patients with secondary immune dysregulation. Thus, the analysis of BALF might be of diagnostic value not only in the diagnosis of CVID-ILD, but also in the evaluation of the activity of the disease and in determining potential treatment targets confirming the prominent role of B-cell targeted strategies.

scholarly journals Critical Role of T Cells in PF4/Heparin Antibody Production

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1554-1554
Author(s):  
Yongwei Zheng ◽  
Mei Yu ◽  
Anand Padmanabhan ◽  
Richard H. Aster ◽  
Renren Wen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Cd4 T Cells ◽  
Wild Type ◽  
Specific Antibodies ◽  
Deficient Mice

Abstract Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that can cause arterial or venous thrombosis/thromboembolism, and platelet factor 4 (PF4)/ heparin-reactive antibodies are essential to the pathogenesis of HIT. Our recent studies have demonstrated that marginal zone (MZ) B cells play a major role in production of PF4/heparin-specific antibodies. However, the role of T cells in production of these pathogenic antibodies is not clear. Here we showed that PF4/heparin complex-induced production of PF4/heparin-specific antibodies was markedly impaired in mice, in which CD4 T cells were depleted by administration of GK1.5 anti-CD4 monoclonal antibody. As expected, the CD4 T cell-depleted mice responded normally to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, in agreement with the lack of CD4 T cells in these GK1.5-treated mice. Further, following adoptive transfer of a mixture of wild-type splenic B cells and splenocytes from B cell-deficient μMT mice, T and B cell-deficient Rag1 knockout mice responded to PF4/heparin complex challenge to produce PF4/heparin-specific antibodies. In contrast, Rag1-deficient mice that received a mixture of wild-type splenic B cells and splenocytes from Rag1-deficient mice barely produced PF4/heparin-specific antibodies upon PF4/heparin complex challenge. These data suggest that T cells are required for production of PF4/heparin-specific antibodies. Consistent with this concept, mice with B cells lacking CD40 molecule, a B cell costimulatory molecule that helps T cell-dependent B cell responses, displayed a marked reduction of PF4/heparin-specific antibody production following PF4/heparin complex challenge. Also as expected, mice with CD40-deficient B cells were able to respond to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, consistent with the lack of T-cell help in these mice. Taken together, these findings demonstrate that T cells play an essential role in production of PF4/heparin-specific antibodies by MZ B cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intratumoral T cells have a differential impact on FDG-PET parameters in follicular lymphoma

2021 ◽  
Vol 5 (12) ◽  
pp. 2644-2649
Author(s):  
Karthik Nath ◽  
Soi-Cheng Law ◽  
Muhammed B. Sabdia ◽  
Jay Gunawardana ◽  
Lilia M. de Long ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Glucose Uptake ◽  
Fdg Pet ◽  
Prognostic Impact ◽  
The Impact

Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell–depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL.

scholarly journals The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Caterina Veroni ◽  
Francesca Aloisi
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Epstein Barr

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

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