Signal Thresholds and Modular Synergy During Expression of Costimulatory Molecules in B Lymphocytes

Natarajan, Krishnamurthy; Sahoo, N. C.; Rao, Kanury V. S.

doi:10.4049/jimmunol.167.1.114

Cited by 22 publications

(23 citation statements)

References 50 publications

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“…Stimulated cells produced 10-to 20-fold more IL-10 than unstimulated cells. Note that in BCR-activated cells, 22,23 CD86 was induced as expected in all 3 populations after 48 hours of stimulation (Figure 1, bottom). CD5 was also up-regulated on B cells, especially in the B-cell population that already expressed CD5 before stimulation (MFI, 93.29).…”

Section: Cd5 ؉ Peripheral B Cells Produce More Il-10 Than Cd5 ؊ B Cellsmentioning

confidence: 97%

“…The lack of expression of CD80 and CD86 activation markers 22,23 ruled out the possibility that CD5 ϩ B cells represented a predominantly activated subpopulation. Next, total purified B cells in bulk were stimulated or not stimulated with anti-IgM ϩ CD40 ligand trimer and were reanalyzed for the expression of CD5 and CD86.…”

Section: Cd5 ؉ Peripheral B Cells Produce More Il-10 Than Cd5 ؊ B Cellsmentioning

confidence: 99%

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Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Gary-Gouy

Harriague

Bismuth

et al. 2002

Blood

180

158

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IntroductionCD5 is a lymphoid marker-one of the earliest acquired during T-cell ontogeny. Its expression increases coordinately with that of cell surface CD3. 1 Although expressed on lymphoid-committed progenitors, its expression is lost following natural killer (NK) cell differentiation. 2 In contrast to its being a pan-T-cell marker, CD5 is only expressed on some B cells. Based on its coexpression with CD11b, immunogloublin M (IgMϩ) B cells in mouse and human are classically separated into different subsets, termed B-1a and B-1b, each of which expresses CD11b and B-2. 3 The B-1a subset expresses CD5, and at a functional level these CD5 ϩ B cells frequently produce polyreactive antibodies, mainly IgM, that recognize a variety of self-antigens and foreign antigens. 4 The reason for the expression of CD5 on a particular B-cell subsetsomething Wortis and Berland 5 call "one of many intriguing and seemingly idiosyncratic features of B-1a cells"-has remained obscure. Two hypotheses are proposed to explain the origin of B-1 cells. The lineage hypothesis holds that only certain fetal progenitors are destined to become B-1 cells. 6,7 In contrast, the differentiation hypothesis holds that every B cell is able to acquire B-1 cell characteristics. In brief, the notion of B-cell lineage based on differential CD5 expression is controversial because of the lack of clear identification of a fetal progenitor destined to become a B-1 B cell and the demonstration that CD5 Ϫ cells can acquire CD5 expression in vivo 8 or in vitro 9 after B-cell receptor (BCR) stimulation This up-regulation supports the initial view that CD5 is an activation marker 10 ; however, a definitive function for this antigen remains to be established.It has been shown that CD5 up-regulation in B cells plays a role in tolerance to autoantigens. By setting the threshold level for activation signals, CD5 prevents B cells from activation-induced cell death and maintains tolerance in anergic B cells in vivo. 11 The reason for keeping potentially autoreactive cells alive is that these cells are also necessary for an effective immune response to some pathogens. 12 This supported the role of CD5 as a negative regulator of BCR signaling, which was later demonstrated by the generation of CD5-null mice. 13 In these animals, peritoneal B cells, which are poorly responsive to BCR stimulation, restored their capacity to fully proliferate to anti-IgM. 13 The molecular basis for BCR inhibition by CD5 has been extensively investigated. The physical association of CD5 to the BCR was demonstrated, 14 and our recent work further documented the structural basis of CD5 inhibition of BCR-mediated signals. Using a reconstitution approach, in a murine lymphoma B cell line we showed that Ca 2ϩ response, extracellular signal-related kinase-2 (ERK-2) activation, and the production of interleukin-2 (IL-2) induced by BCR activation were antagonized by CD5. 15 The role of the src autophosphorylationlike motif within the cytoplasmic domain was demonstrated. 16 Of interest, this domain is...

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Section: Cd5 ؉ Peripheral B Cells Produce More Il-10 Than Cd5 ؊ B Cellsmentioning

confidence: 97%

Section: Cd5 ؉ Peripheral B Cells Produce More Il-10 Than Cd5 ؊ B Cellsmentioning

confidence: 99%

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Gary-Gouy

Harriague

Bismuth

et al. 2002

Blood

180

158

View full text Add to dashboard Cite

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“…Intracellular calcium levels were monitored essentially as previously described (25). Briefly, either 2 ϫ 10 7 GM-CSF-DCs or MTSA-DCs were loaded with 1 M fluo-3-AM for 45 min at 37°C in culture medium.…”

Section: Estimation Of Intracellular Calcium Levelsmentioning

confidence: 99%

Impaired Generation of Reactive Oxygen Species during Differentiation of Dendritic Cells (DCs) byMycobacterium tuberculosisSecretory Antigen (MTSA) and Subsequent Activation of MTSA-DCs by Mycobacteria Results in Increased Intracellular Survival

Sinha

Singh

Satchidanandam

et al. 2006

The Journal of Immunology

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We investigated the role of reactive oxygen species (ROS) in dendritic cell (DC) differentiation by 10-kDa Mycobacterium tuberculosis secretory Ag (MTSA) and survival of mycobacteria therein. Compared with GM-CSF, MTSA induced lower ROS production during DC differentiation from precursors. This result correlated with higher superoxide dismutase 1 expression in MTSA stimulated precursors as compared with GM-CSF stimulation. Furthermore, a negative regulation of protein kinase C (PKC) activation by ROS was observed during DC differentiation. ROS inhibited the rapid and increased phosphorylation of PKCα observed during DC differentiation by MTSA. In contrast, ROS inhibition increased the weak and delayed PKCα phosphorylation by GM-CSF. Similar to DC differentiation, upon activation with either M. tuberculosis cell extract (CE) or live Mycobacterium bovis bacillus Calmette-Guérin (BCG), DCs differentiated with MTSA (MTSA-DCs) generated lower ROS levels when compared with DCs differentiated with GM-CSF (GM-CSF-DCs). Likewise, a negative regulation of PKCα phosphorylation by ROS was once again observed in DCs activated with either M. tuberculosis CE or live M. bovis BCG. However, a reciprocal positive regulation between ROS and calcium was observed. Compared with MTSA-DCs, stimulation of GM-CSF-DCs with M. tuberculosis CE induced a 2-fold higher ROS-dependent calcium influx. However, pretreatment of MTSA-DCs with H2O2 increased calcium mobilization. Finally, lower ROS levels in MTSA-DCs correlated with increased intracellular survival of M. bovis BCG when compared with survival in GM-CSF-DCs. Although inhibiting ROS in GM-CSF-DCs increased M. bovis BCG survival, H2O2 treatment of MTSA-DCs decreased survival of M. bovis BCG. Overall our results suggest that DCs differentiated with Ags such as MTSA may provide a niche for survival and/or growth of mycobacteria following sequestration of ROS.

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“…For some experiments, cells were cultured with 15 ng/ml of GM-CSF for 4 days. Cells at the end of incubation in all sets were either analyzed for the levels of surface molecules by flow cytometry, as described before (22), or cocultured with either allogeneic or Ag-primed syngeneic T cells, as described below. The cell yield and viability of each culture were estimated by trypan blue exclusion and counting.…”

Section: Enrichment Of DC Precursors From Bmmentioning

confidence: 99%

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

Latchumanan

Singh

Sharma

et al. 2002

The Journal of Immunology

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We show in this study that incubation of freshly isolated bone marrow cells with Mycobacterium tuberculosis (M. tb) secretory Ag (MTSA), in the absence of any growth or differentiation-inducing factor, differentiates them into dendritic cell (DC)-like APCs. These DCs expressed moderate to high levels of various markers typical of DCs. These included T cell costimulatory molecules CD80, CD86, CD40, and CD54 and high levels of surface MHC class I and II on CD11c+ cells. The levels and the kinetics of up-regulation of these molecules were comparable with those of GM-CSF-differentiated DCs. Furthermore, these DCs exhibited morphology characteristics to DCs like the presence of dendritic processes. These DCs were also potent stimulators of allogeneic T cells and preferentially induced the secretion of IFN-γ over IL-10 from the interacting T cells. Interestingly, the differentiation of bone marrow cells into DC-like APCs was obtained with many other M. tb Ags, including whole cell extract of M. tb. Further characterization of MTSA-differentiated DCs showed that they were immature in nature, as stimulation of these DCs with TNF-α, anti-CD40, or LPS further up-regulated the surface levels of various molecules together with an increase in their T cell stimulatory capacity. The Ag-specific T cell responses of MTSA-differentiated DCs were mainly contributed by the CD4+ subset, indicating that MTSA was largely MHC II restricted. Furthermore, stimulation of bone marrow cells with MTSA induced the nuclear translocation of the transcription factor NF-κB, thereby indicating its role during MTSA-induced differentiation of DCs.

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Signal Thresholds and Modular Synergy During Expression of Costimulatory Molecules in B Lymphocytes

Cited by 22 publications

References 50 publications

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Impaired Generation of Reactive Oxygen Species during Differentiation of Dendritic Cells (DCs) byMycobacterium tuberculosisSecretory Antigen (MTSA) and Subsequent Activation of MTSA-DCs by Mycobacteria Results in Increased Intracellular Survival

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

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