The Biological Outcome of CD40 Signaling Is Dependent on the Duration of CD40 Ligand Expression

Lee, Byung O.; Haynes, Laura; Eaton, Sheri M.; Swain, Susan L.; Randall, Troy D.

doi:10.1084/jem.20020845

Cited by 90 publications

(104 citation statements)

References 64 publications

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“…6) is in accordance with the CD154 expression found in mouse CD4 T cells, which demonstratedly occurs in two phases (Lee et al 2002). The early phase of CD154 expression occurs within hours of the T-cell activation and is regulated independently of the local cytokine milieu (Lee et al 2002).…”

Section: Discussionsupporting

confidence: 81%

“…In this phase, the CD154 expression diminishes rapidly and is undetectable within 12-24 h after activation. However, the second phase of CD154 expression occurs between 24 and 72 h and is highly dependent on cytokines (Skov et al 2000;Lee et al 2002;Snyder et al 2007) and costimulatory molecules (Jenkins and Johnson 1993;Kaminski et al 2009), which can sustain CD154 expression for several days.…”

Section: Discussionmentioning

confidence: 99%

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Co-culture of the 55-6 B cell hybridoma with the EL-4 thymoma cell. Effect on cell growth and monoclonal antibody production

et al. 2013

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The cell growth and monoclonal antibody production of the 55-6 hybridoma cell co-cultured with the murine thymoma cell line EL-4 at different initial 55-6:EL-4 ratios were investigated. Both populations were seeded in co-culture without previous stimulation and therefore with low constitutive CD40 and CD40 ligand (CD154) expression levels, and in the absence of exogenous co-stimuli. Viable cell density and growth rate data seem to suggest a competition for nutrients, which is detrimental for both cells in terms of biomass production and also of growth rate for 55-6. Final concentrations of antibody and specific antibody production rates were affected by the initial 55-6:EL-4 ratio. The 4:1 ratio yielded the highest IgG2a concentration, whereas the highest specific antibody production rate was obtained at the 2:1 ratio. Changes mainly in CD154 and also in CD40 expression in cocultures could suggest cross-talk between both populations. In conclusion, different types of interactions are probably present in this co-culture system: competition for nutrients, cognate interaction and/or autocrine or paracrine interactions that influence the proliferation of both cells and the hybridoma antibody secretion. We are hereby presenting a pre-scale-up process that could speed up the optimization of largescale monoclonal antibodies production in bioreactors by emulating the in vivo cell-cell interaction between B and T cells without previous stimulation or the addition of co-stimulatory molecules.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Co-culture of the 55-6 B cell hybridoma with the EL-4 thymoma cell. Effect on cell growth and monoclonal antibody production

et al. 2013

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“…It has been recently reported that the two phases of CD154 expression are differentially regulated; the first stage being responsive to signaling through the TCR and the second phase being modulated by IL-4 and IL-12 cytokines (62). We have yet to analyze CD154 mRNA stability under these different conditions of stimulation.…”

Section: Discussionmentioning

confidence: 99%

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

Kosinski

Laughlin

Singh

et al. 2003

The Journal of Immunology

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CD40 ligand (CD154) expression has been shown to be regulated, in part, at the posttranscriptional level by a pathway of “regulated instability” of mRNA decay throughout a time course of T cell activation. This pathway is modulated at late times of activation by the binding of a stability complex (termed complex I) to a CU-rich region in the 3′ untranslated region of the CD154 message. We have undertaken experiments to extend these findings and to analyze the cis-acting elements and trans-acting factors involved in this regulation. We have previously shown that the minimal binding sequence for complex I is a 63 nt CU-rich motif. However, our current study shows that when this site was deleted additional complex binding was observed upstream and downstream of the minimal binding region. Only after deletion of an extended region (termed Δ1515) was complex binding completely abolished. Analysis of complex binding using competition experiments revealed that the three adjacent regions bound related but not identical complexes. However, all three sites appeared to have a 55-kDa protein as the RNA-binding protein. Deletion of the Δ1515 region resulted in reduced transcript stability as measured by both in vitro and in vivo decay assays. Finally, using Abs against known RNA-binding proteins, we identified the polypyrimidine tract-binding protein (or heterogeneous nuclear ribonucleoprotein I) as a candidate RNA-binding component of complex I.

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“…A recent study demonstrated that CD40L expression on CD4 ϩ T cells can be separated into an early TCR-dependent phase and a later extended phase, and that the biological outcome of CD40 signaling for B cells depends upon the duration of interaction (27). Interestingly, only Th1 CD4 ϩ T cells exhibit a later extended phase.…”

Section: Endritic Cells (Dcs) 2 Are Believed To Be the Most Potentmentioning

confidence: 99%

The Duration of Signaling through CD40 Directs Biological Ability of Dendritic Cells to Induce Antitumor Immunity

Watanabe

Kagamu

Yoshizawa

et al. 2003

The Journal of Immunology

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Although it has been demonstrated that the functions of dendritic cells (DCs), including Ag capture, Ag presentation, and migratory activity, change dynamically with their maturation, the most appropriate conditioning of DCs for anticancer immunotherapy is still unclear. The help signal is one of the most potent stimuli for DC maturation and is provided by the interaction of CD40 expressed on DCs with CD40 ligand on CD4+ T cells. To elucidate the appropriate conditioning of DCs for anticancer immunotherapy, we examined the biological activity of DCs stimulated with immobilized anti-CD40 Ab. DCs stimulated for 3 h (3h-DCs) still showed an immature phenotype, but exhibited augmented migration toward secondary lymphoid tissues. Subcutaneous injection of 3h-DCs facilitated priming of T cells, which could mediate potent antitumor therapeutic efficacy, in draining lymph nodes and successfully induced protective immunity. In contrast, 24h-DCs showed a mature phenotype with good Ag presentation ability to induce cell killing by adoptively transferred CD8+ T cells when injected at tumor sites; however, they showed no migratory activity and were unable to induce protective immunity when injected s.c.. This is the first report that functionally distinct DCs, either for the priming phase or for the effector phase, could be obtained by conditioning with CD40 stimulation and that the duration of stimulation determines the biological outcome. The usage of DCs conditioned for the priming phase might provide significant advantages in anticancer immunotherapy.

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The Biological Outcome of CD40 Signaling Is Dependent on the Duration of CD40 Ligand Expression

Cited by 90 publications

References 64 publications

Co-culture of the 55-6 B cell hybridoma with the EL-4 thymoma cell. Effect on cell growth and monoclonal antibody production

Co-culture of the 55-6 B cell hybridoma with the EL-4 thymoma cell. Effect on cell growth and monoclonal antibody production

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

The Duration of Signaling through CD40 Directs Biological Ability of Dendritic Cells to Induce Antitumor Immunity

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