T cell priming by dendritic cells: thresholds for proliferation, differentiation and death and intraclonal functional diversification (original) (raw)
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European Journal of Immunology, 2006
Dendritic cell (DC) maturation influences the priming and polarization of T lymphocytes. We recently found that early activated DC (i.e. DC exposed to promaturation stimuli for 8 h) were more prone to prime in vivo a type-1 cytotoxic T cell (Tc1) response than DC exposed to pro-maturation stimuli for 48 h (48h-DC). We investigated whether 48h-DC, conversely, allowed the induction of Tc2 cells. Antigenpulsed mouse bone-marrow-derived DC at any maturation stage, in the presence of exogenous IL-12, skewed in vitro naive CD8 + T cells towards Tc1 cells, but 48h-DC most potently, in the presence of exogenous IL-4, favored the induction of Tc2 cells. In vivo, full maturation of DC promoted expansion of Tc2 and fall of Tc1 cells. Tc2 cells maintained a high cytolytic activity and produced significant amounts of IL-4, IL-5, IL-10 and TGF-b. Our results indicate that polarization of naive CD8 + T cells to Tc2 cells is dependent on the amount of time DC have been exposed to maturation stimuli, and might be favored in late and/or chronic phases of an immune response.
Nature Immunology, 2005
The maturation status of dendritic cells (DCs) determines whether they prime or tolerize T cells. We targeted ovalbumin peptide exclusively to DCs in situ using an antibody to DEC-205 and studied the interaction of DCs with naive CD4 + T cells in tolerizing or priming conditions. We used two-photon microscopy to simultaneously track antigen-specific OT-II T cells, nonspecific T cells and DCs in lymph nodes of living mice. In both tolerance and immunity, OT-II cells arrested on DCs near high endothelial venules beginning shortly after extravasation and regained their baseline speed by 18 h. Thus, early antigen-dependent T cell arrest on DCs is a shared feature of tolerance and priming associated with activation and proliferation.
Journal of Experimental Medicine, 2002
Strong antigenic encounter by T cells rapidly induces immunological synapse formation and surface T cell receptor (TCR) downregulation. Although surface TCR expression can remain low for several days, T cells can still sustain antigenic signaling. It has been unclear whether prolonged antigenic signaling occurs in the absence of surface TCR replenishment, being maintained by a few "nondownregulatable" surface TCRs that might reside in a synaptosomal structure. Alternatively, the low surface TCR level induced by antigen might represent a dynamic state of expression involving continual surface TCR replenishment, reengagement by antigen, and ongoing downregulation. To resolve this issue, we studied in vivo-generated, dual-specificity primary naive CD4 ϩ T cells. On these cells, antigenic stimulus exclusively downregulated antigen-specific, but not antigen-nonspecific, TCRs. In addition to providing a means to track TCR engagement, this also allowed us to use the antigen nonspecific TCR to track TCR expression in isolation from TCR engagement by antigen. Surface TCR replenishment began within the first day of stimulation, and occurred synchronously with continuous antigen-specific TCR engagement and downregulation. Furthermore, by enhancing CD25 expression, extended signaling through surface-replenishing TCRs significantly amplified the number of daughter cells generated by naive CD4 ϩ T cells that had already committed to proliferate. This effect required TCR engagement and could not be substituted for by interleukin 2. These data demonstrate that TCR triggering and consumption can occur over an extended period of time, with a significant impact on the effector responses evoked from naive CD4 ϩ T cells.
Journal of Experimental Medicine, 2000
The well defined, immature murine dendritic cell (DC) line D1 was used to study the role of DC maturation in CTL induction in vitro and in vivo. Maturation of D1 cells, characterized by markedly increased expression of MHC and costimulatory molecules, was induced by incubation with lipopolysaccharide, agonistic CD40 antibody, or specific CD4 ϩ T helper (Th) cells. Activated, but not immature, D1 cells efficiently primed alloreactive T cell responses in vitro. Similarly, priming of CTL immunity in vivo in CD4-depleted mice was only observed if these mice were immunized with activated D1 cells. This study provides formal evidence that activation of DCs, induced by Th-independent as well as Th-dependent stimuli, is essential for efficient induction of CTL responses.
Clinical Immunology, 2008
After homing to lymph nodes, CD8 + T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.
International Immunology, 2006
CD8 1 splenic dendritic cells (DCs) from steady-state mice are less effective than the CD8 ÿ DC subset in their capacity to stimulate CD4 T cell proliferation in culture. However, we found that the two DC subtypes were equally potent at activating CD4 T cells, based on up-regulation of CD69 and CD25 expression. Also, we found no difference in the rate of T cell death prior to entry into the first division. We then tracked carboxyfluorescein diacetate succinimidyl ester-labeled T cells and employed a quantitative model to assess in detail the CD4 T cell expansion process in response to stimulation with CD8 1 or with CD8 ÿ DCs. The time required for most T cells to replicate their DNA prior to the first division was similar in both DC cultures. However, progression of the CD4 T cell population through subsequent divisions was reduced in CD8 1 DCs compared with CD8 ÿ DC culture. This was associated with an increased loss of viable T cells at each division. Post-activation, division-associated T cell death is therefore a major factor in the reduced response of CD4 T cells to CD8 1 DCs. by guest on December 21, 2015 http://intimm.oxfordjournals.org/ Downloaded from CD8 + DCs restrict CD4 T cell proliferation 423 by guest on December 21, 2015 http://intimm.oxfordjournals.org/ Downloaded from
Immunology, 2003
Antigenic encounter by T cells induces immunological synapse formation and T-cell activation. Using different concentrations of toxic shock syndrome toxin-1 (TSST-1) as stimulus, we examined the capacities of dendritic cells (DC) and macrophages (Mf) to prime syngeneic naive T cells. DCs were, under all experimental settings, more ef®cient than Mf at clustering T cells. Translocation of the T-cell receptor (TCR) to the contact area was found to be induced by DCs, as well as by Mf, in an antigen-dependent manner, although Mf were less ef®cient at inducing TCR translocation. Capping of protein kinase C u (PKCu) was also antigen dependent but induced exclusively by DCs. Likewise, DCs were found to be more potent inducers of interleukin-2 (IL-2) production and proliferation of naive T cells than Mf. After 3 days of culture, DCs presenting 100 ng/ml TSST-1 induced interferon-g (IFN-g)-secreting cells, whereas Mf did not. After 7 days of culture, DCs presenting 0Á1 ng/ml TSST-1, and Mf presenting high (as well as low) doses of TSST-1, induced IL-4-producing cells. We therefore provide evidence to show that antigen dose, type of antigen-presenting cell and time of differentiation can contribute to T-cell differentiation.
Bacterial Superantigens Dendritic Cells in Response to T Cell-Dependent Maturation of
2000
Dendritic cells (DC) express a set of germline-encoded transmembrane Toll-like receptors that recognize shared microbial products, such as Escherichia coli LPS, termed pathogen-associated molecular patterns. Analysis of the in vivo response to pathogenassociated molecular patterns has uncovered their ability to induce the migration and the maturation of DC, favoring thus the delivery of Ag and costimulatory signals to naive T cells in vivo. Bacterial superantigens constitute a particular class of pathogenderived molecules known to induce a potent inflammatory response in vivo, secondary to the activation of a large repertoire of T cells. We demonstrate in this work that Staphylococcal superantigens induce migration and maturation of DC populations in vivo. However, in contrast to LPS, superantigens failed to induce DC maturation in RAG or MHC class II-deficient mice, suggesting that T cell activation was a prerequisite for DC maturation. This conclusion was further supported by the finding that T cell activation induced by 1) mitogenic anti-CD3 mAbs, 2) allo-MHC determinants, or 3) nominal Ag in a TCR-transgenic model induces DC maturation in vivo. These studies also revealed that DC that matured in response to T cell mitogens display, comparatively to LPS, a distinctive phenotype characterized by high expression of the MHC class II, CD40, and CD205 markers, but only moderate (CD86) to minimal (CD80) expression of CD28/CTLA4 ligands. This work demonstrates that activation of a sufficient number of naive T cells in vivo constitutes a novel form of immune danger, functionally linked to DC maturation.