CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86

  title={CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86},
  author={Ciriana Orabona and Ursula Grohmann and Maria Laura Belladonna and Francesca Fallarino and Carmine Vacca and Roberta Bianchi and Silvia Bozza and Claudia Volpi and Beno{\^i}t L. Salomon and Maria Cristina Fioretti and Luigina Romani and Paolo Puccetti},
  journal={Nature Immunology},
Bidirectional signaling along the B7–CTLA-4 coreceptor pathway enables reciprocal conditioning of T cells and dendritic cells. Although T cells can instruct dendritic cells to manifest tolerogenic properties after CTLA-4 engagement of B7, such a B7-mediated signaling is not known to occur in response to CD28. Here we show that mouse dendritic cells were induced by soluble CD28 to express interleukin 6 and interferon-γ. Production of interleukin 6 required B7-1 (CD80), B7-2 (CD86) and p38… 


The role of DCs matured under conditions mimicking acute/early inflammation or mimicking chronic/late inflammation on the differentiation of CD8+ T cells is analyzed, widening the understanding of the mechanisms of DC-induced effector and memory cell differentiation and might lead to the improved DC-based cancer vaccines.

Cutting Edge: Silencing Suppressor of Cytokine Signaling 3 Expression in Dendritic Cells Turns CD28-Ig from Immune Adjuvant to Suppressant1

It is shown that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFn-γ signaling and IFN-γ-like actions of IL-6.

Cross-Linking of CD80 on CD4+ T Cells Activates a Calcium-Dependent Signaling Pathway1

A novel regulatory role for CD80-mediated intracellular signals in CD4+ T cells is indicated and have important implications for disease therapies using anti-costimulatory mAbs as use of an intact CD80 mAb may lead to CD80 cross-linking on activated T cells and enhanced proinflammatory cytokine production.

Influence of CD80 and CD86 Co-Stimulation in the Modulation of the Activation of Antigen Presenting Cells

It may be concluded that CD28/CD152-CD80/86 interaction delivers a bi-directional co-stimulation, thereby not only having impact on the function of T cells, but also an- tigen presenting cells.

Costimulation and T cells as therapeutic targets

It is suggested that CTLA-4 can actively dampen T cell activation both by direct effects on the T cell and also by effects on APCs, which would have secondary effects on key diseaserelated cytokines.

Regulatory T Cells + CD25+ CD4Homing Potential through Interaction with Semimature Phenotype and Lymph Node Human Dendritic Cells Acquire a

The data show that Tregs induce the generation of semimature DC with the potential to migrate into lymphoid organs, suggesting a possible mechanism by which T Regs down-modulate immune responses.

CTLA4Ig Inhibits Effector T Cells through Regulatory T Cells and TGF-β

In addition to preventing naive T cells from being fully activated, CTLA4Ig can turn off already activated effector T cells by an NO/regulatory T cell/TGF-β–dependent pathway, which may be particularly important in the ability of CTLA 4Ig to treat chronic inflammatory disease.

Combinatorial Signaling through TLR-2 and CD86 Augments Activation and Differentiation of Resting B Cells

This study elucidates a novel BCR independent B cell activation mechanism that links TLR-2 and CD86, and indicates signaling of TLRs in conjunction with costimulatory molecules will substantially help in bolstering humoral immune response, which can be extrapolated to formulate vaccination strategies for diseases involving B cell-mediated immunity.

Reverse signaling using an inducible costimulator to enhance immunogenic function of dendritic cells

This study shows that the interaction of ICOSIg and its ligand (ICOSL) on mouse bone marrow-derived dendritic cells (DCs) induces a p38-MAPK dependent elevation of interleukin 6 (IL-6) and also enhances phagocytosis and the antigen-presentation function of DCs in vitro, further favoring cell-mediated immunity in vivo.

Mechanisms of CTLA-4-Ig in tolerance induction.

Fusion proteins between the extracellular domain of CTLA-4 and an immunoglobulin Fc portion have been created that have potent immunosuppressive properties in animal models of transplantation and autoimmunity and that show great promise in clinical trials.



CD40 Ligation Ablates the Tolerogenic Potential of Lymphoid Dendritic Cells1

In vivo, not only did CD40 triggering on lymphoid DC abrogate their tolerogenic activity, but it also induced the potential for immunogenic presentation of P815AB, a tolerogenic tumor/self peptide.

B7-1 Engagement of Cytotoxic T Lymphocyte Antigen 4 Inhibits T Cell Activation in the Absence of CD28

CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.

Differential T cell costimulatory requirements in CD28-deficient mice.

CD28 is not required for all T cell responses in vivo, suggesting that alternative costimulatory pathways may exist.

IL-6 Inhibits the Tolerogenic Function of CD8α+ Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase1

IL-6 may both replace (upon administration of the recombinant cytokine) and mediate (as assessed by the use of neutralizing Abs) the effect of CD40 ligation in ablating the tolerogenic activity of CD8+ DC.

CD28 Function: A Balance of Costimulatory and Regulatory Signals

Evidence is summarized that CD28 is also prominent in the regulation of immune responses and the maintenance of peripheral tolerance, and that caution should be taken in the development of immunotherapies targeting costimulatory pathways.

Persistent Toll-like receptor signals are required for reversal of regulatory T cell–mediated CD8 tolerance

It is demonstrated that virus providesTLR signals required for bypassing regulatory T cell–mediated tolerance and emphasize the importance of persistent TLR signals for immunotherapy in the setting of established tolerance.

IFN-γ Inhibits Presentation of a Tumor/Self Peptide by CD8α− Dendritic Cells Via Potentiation of the CD8α+ Subset1

It is reported here that exposure of CD8+ DC to IFN-γ greatly enhances their inhibitory activity on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8− DC to overcome suppression.

Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells

A second mechanism of immune induction by TLRs is described, which is independent of effects on costimulation, and dependent in part on interleukin-6, which was induced byTLRs upon recognition of microbial products.

The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens

It is shown that initiation of T cell responses requires the expression of B7 on immunizing APCs, but the responses are much greater in the absence of basal B7 expression, thereby inducing autoimmunity.

CD28/B7 system of T cell costimulation.

This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to the current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28-mediated T cell and B cell regulation.