scholarly journals Dominant Role of CD80–CD86 Over CD40 and ICOSL in the Massive Polyclonal B Cell Activation Mediated by LATY136F CD4+ T Cells

2012 ◽  
Vol 3 ◽  
Author(s):  
Stéphane Chevrier ◽  
Céline Genton ◽  
Bernard Malissen ◽  
Marie Malissen ◽  
Hans Acha-Orbea
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Dominant Role ◽  
B Cell Activation

scholarly journals Thymic stromal lymphopoietin (TSLP)-induced polyclonal B-cell activation and autoimmunity are mediated by CD4+ T cells and IL-4

2012 ◽  
Vol 24 (3) ◽  
pp. 183-195 ◽  
Author(s):  
M. Iseki ◽  
M. Omori-Miyake ◽  
W. Xu ◽  
X. Sun ◽  
S. Takaki ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Thymic Stromal Lymphopoietin ◽  
B Cell Activation

scholarly journals T Cell‐Dependent B Cell Activation Mediates Pathophysiology in Reponse to CD4 + T Cells from Reduced Uterine Perfusion Pregnant Rats

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Denise Cornelius ◽  
Javier Castillo ◽  
Lorena Amaral ◽  
Kedra Wallace ◽  
Janae Moseley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
B Cell Activation ◽  
Pregnant Rats ◽  
Uterine Perfusion

scholarly journals Activated CLL B Cells Variably Modulate microRNA-155 Levels in Naïve CD4+ T Cells, and the Direction and Magnitude of microRNA-155 Change Correlates with Th17 Levels and Clinical Course

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4402-4402
Author(s):  
Byeongho Jung ◽  
Gerardo Ferrer ◽  
Pui Yan Chiu ◽  
Rukhsana Aslam ◽  
Florencia Palacios ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
B Cell Activation ◽  
Mutation Status ◽  
Naive T Cells ◽  
Naïve T Cells

Abstract T-helper 17 (Th17) cells constitute a subset of T cells that characteristically secrete IL-17. In addition to their normal adaptive immune functions, Th17 cells also play roles in supporting dysfunctional immune responses found in autoimmunity and cancer. Several studies suggest that Th17 cells play a protective role in chronic lymphocytic leukemia (CLL). For example, CLL patients exhibit varied levels of circulating Th17 cells, and elevated levels positively correlate with better clinical outcome regardless of IGHV-mutation status. To understand this relationship and elucidate the cellular and molecular mechanisms of Th17 generation in CLL, in particular the role of microRNAs known to affect Th17 development, we investigated cross-talk between naïve CD4+ T cells and CLL B cells. Moreover, since intraclonal leukemic B-cell subpopulations differing in time since cell birth/division can exhibit different functional effects on antigen presentation, we explored the effect of B-cell activation on this T - leukemic B-cell dialogue and how it affects the generation of Th17 cells. To determine potential candidates differentially expressed in CLL, we conducted genome-wide single-cell expression analysis comparing fluorescence activated cell sorting (FACS)-purified mature Th17 cells (CD3+/CD4+/CD45+/CD161+/CCR6+/ CCR4+/CXCR3-) from CLL patients and healthy donors. Selected candidate genes met the criteria of >7-fold increase in expression in CLL, adjusted p-value <1.5 x 10-6, and link to lymphocyte biology. Among selected candidates, microRNA-155 (miR-155), a critical regulator of Th17 differentiation, was found. Follow-up real time, quantitative PCR (RT-qPCR) analyses indicated a significant increase (P < 0.01) in miR-155 expression in CLL Th17 cells as compared to Th17 cells from healthy controls. Since there was no difference in expression between naïve T cells (CD3+/CD4+/CD62L+/CD45RO-) cells, this suggested a CLL-unique mechanism of miR-155 modulation. To determine whether CLL cells directly influence miR-155 levels in naïve CD4+ T cells, co-culture experiments using autologous leukemic or healthy B cells were carried out. FACS-purified peripheral blood naïve CD4+ T cells and B cells from CLL patients and from age-matched healthy controls were co-cultured for 3 days, and expression of T-cell miR-155 was determined by RT-qPCR. In the presence of unstimulated CLL or healthy B cells, miR-155 expression in naïve T cells remained unchanged across all co-cultures. However, upon activation, healthy and leukemic B cells exerted differential effects on miR-155 expression in autologous naïve T cells. In the presence of autologous healthy B cells pre-activated with CpG-ODN2006 and IL-15, miR-155 expression in healthy naïve T cells was significantly increased (P = 0.0313) across all samples. Conversely, CLL naïve T cells co-cultured with autologous, pre-activated leukemic B cells showed heterogeneous modulation of miR-155. Of interest, the magnitude and direction of miR-155 changes in the autologous CLL co-cultures positively correlated not only with circulating Th17 levels (P = 0.019), as determined by flow cytometry, but also with patient time to first treatment (P = 0.0003). Moreover, when samples were divided into 2 groups based on an increase or decrease in miR-155 levels after exposure to activated compared to resting CLL B cells, a significant difference was seen with median survival of 237 months and 67 months, respectively (P = 0.005). Consistent with previous observations from our lab, this correlation was independent of various prognostic markers, including IGHV-mutation status. Our results suggest the existence of a miR-155 modulatory mechanism mediated by CLL B cells that differs based on leukemic B-cell activation state and the degree of change occurring when naïve T cells are exposed to resting vs. activated B cells. Moreover, this variable effect in CLL patients differs from that in normal individuals, and the effect influences number of Th17 cells and patient outcome. Studies are underway to determine the effects that leukemic B cells, unstimulated or CpG-ODN2006 + IL-15 stimulated, have on autologous naïve T-cell maturation into Th17 cells, and the extent that this process depends on the variable miR-155 modulatory capacity of leukemic B cells. Disclosures Chiorazzi: Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.

scholarly journals Murine Cytomegalovirus Infection-Induced Polyclonal B Cell Activation Is Independent of CD4+T Cells and CD40

Virology ◽  
1998 ◽  
Vol 240 (1) ◽  
pp. 12-26 ◽  
Author(s):  
Gunasegaran Karupiah ◽  
Tamara E. Sacks ◽  
Dennis M. Klinman ◽  
Torgny N. Fredrickson ◽  
Janet W. Hartley ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cytomegalovirus Infection ◽  
Cell Activation ◽  
Murine Cytomegalovirus ◽  
B Cell Activation

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

scholarly journals Lymphoma models for B cell activation and tolerance. X. Anti-mu-mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc.

1994 ◽  
Vol 179 (1) ◽  
pp. 221-228 ◽  
Author(s):  
G Fischer ◽  
S C Kent ◽  
L Joseph ◽  
D R Green ◽  
D W Scott
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Antisense Oligonucleotides ◽  
Growth Regulation ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
B Cell Activation ◽  
Tgf Beta ◽  
B Cell Lymphomas

Treatment of the WEHI-2131 or CH31 B cell lymphomas with anti-mu or transforming growth factor (TGF)-beta leads to growth inhibition and subsequent cell death via apoptosis. Since anti-mu stimulates a transient increase in c-myc and c-fos transcription in these lymphomas, we examined the role of these proteins in growth regulation using antisense oligonucleotides. Herein, we demonstrate that antisense oligonucleotides for c-myc prevent both anti-mu- and TGF-beta-mediated growth inhibition in the CH31 and WEHI-231 B cell lymphomas, whereas antisense c-fos has no effect. Furthermore, antisense c-myc promotes the appearance of phosphorylated retinoblastoma protein in the presence of anti-mu and prevents the progression to apoptosis as measured by propidium iodide staining. Northern and Western analyses show that c-myc message and the levels of multiple myc proteins were maintained in the presence of antisense c-myc, results indicating that myc species are critical for the continuation of proliferation and the prevention of apoptosis. These data implicate c-myc in the negative signaling pathway of both TGF-beta and anti-mu.

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

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