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Bertrand Dubois

Publications and source records attributed to Bertrand Dubois.

10 recordsLinked to original sources
PubMed2006

Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo.

The nature of dendritic cell(s) (DC[s]) that conditions efficient in vivo priming of CD8+ CTL after immunization via epithelial tissues remains largely unknown. Here, we show that myeloid DCs rapidly recruited by adjuvants into the buccal mucosa or skin are essential for CD8+ T cell crosspriming. Recruitment of circulating DC precursors, including Gr1+ monocytes, precedes the sequential accumulation of CD11c+ MHC class II+ DCs in dermis and epithelium via a CCR6/CCL20-dependent mechanism. Remarkably, a defect in CCR6, local neutralization of CCL20, or depletion of monocytes prevents in vivo priming of CD8+ CTL against an innocuous protein antigen administered with adjuvant. In addition, transfer of CCR6-sufficient Gr1+ monocytes restores CD8+ T cell priming in CCR6( degrees / degrees ) mice via a direct Ag presentation mechanism. Thus, newly recruited DCs likely derived from circulating monocytes are responsible for efficient crosspriming of CD8+ CTL after mucosal or skin immunization.

Adjuvants, Immunologic↗
PubMed2005

Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells.

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.

Animals↗
PubMed2005

Deficient contact hypersensitivity reaction in CD4-/- mice is because of impaired hapten-specific CD8+ T cell functions.

Mice deficient in the CD4 molecule (CD4-/-) are widely used to evaluate the requirement for CD4+ T cell help in viral, tumoral, and transplantation immunity. Previous studies, showing that CD4-/- mice develop impaired contact hypersensitivity (CHS) responses, have suggested that CD4+ T cells are required for the optimal induction of this skin inflammatory reaction. other studies have, however, demonstrated that CHS was mediated by CD8+ T cells, without the need for CD4+ T cell help. Here, we show that CD4-/- mice develop a normal delayed-type hypersensitivity response to protein antigen, which is mediated by major histocompatibility molecules class II-restricted CD4-CD8- T cells, but a decreased CHS response to 2,4-dinitro-fluorobenezene. Analysis of the hapten-specific T cell pool demonstrates that priming of CD8+ T cells occurred normally in CD4-/- mice, as assessed by specific proliferative responses and interferon-gamma (IFN-gamma) production of purified CD8+ T cells. Furthermore, CD8+ T cells were able to adoptively transfer a normal CHS reaction. In contrast, total lymph node cells from CD4-/- mice showed decreased IFN-gamma production and diminished specific cytotoxic T lymphocytes (CTL) activity, which could be reversed by in vitro restimulation with hapten-pulsed class II-deficient antigen-presenting cells. These data confirm that class I-restricted CD8+ T cells can fully develop in effectors of CHS in the absence of CD4+ T cell help and suggest that the impaired CHS in CD4-/- mice is because of the presence of a class II-restricted T cell subset, which controls CHS by inhibiting hapten-specific CTL responses.

Animals↗
PubMed2004

Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response.

Activation of dendritic cells (DC) by microbial products via Toll-like receptors (TLR) is instrumental in the induction of immunity. In particular, TLR signaling plays a major role in the instruction of Th1 responses. The development of Th2 responses has been proposed to be independent of the adapter molecule myeloid differentiation factor 88 (MyD88) involved in signal transduction by TLRs. In this study we show that flagellin, the bacterial stimulus for TLR5, drives MyD88-dependent Th2-type immunity in mice. Flagellin promotes the secretion of IL-4 and IL-13 by Ag-specific CD4(+) T cells as well as IgG1 responses. The Th2-biased responses are associated with the maturation of DCs, which are shown to express TLR5. Flagellin-mediated DC activation requires MyD88 and induces NF-kappaB-dependent transcription and the production of low levels of proinflammatory cytokines. In addition, the flagellin-specific response is characterized by the lack of secretion of the Th1-promoting cytokine IL-12 p70. In conclusion, this study suggests that flagellin and, more generally, TLR ligands can control Th2 responses in a MyD88-dependent manner.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Lactobacillus casei reduces CD8+ T cell-mediated skin inflammation.

Probiotics, including Lactobacilli, have been postulated to alleviate allergic and inflammatory diseases, but evidence that they exert an anti-inflammatory effect by immune modulation of pathogenic T cell effectors is still lacking. The aim of this study was to examine whether L. casei could affect antigen-specific T cell-mediated skin inflammation. To this end, we used contact hypersensitivity to the hapten 2,4-dinitrofluorobenzene, a model of allergic contact dermatitis mediated by CD8+ CTL and controlled by CD4+ regulatory T cells. Daily oral administration of fermented milk containing L. casei or L. casei alone decreased skin inflammation by inhibiting the priming/expansion of hapten-specific IFN-gamma-producing CD8+ effector T cells. The down-regulatory effect of the probiotics required the presence of CD4+ T cells, which control the size of the hapten-specific CD8+ T cell pool primed by skin sensitization. L. casei cell wall was as efficient as live L. casei to regulate both the CHS response and the hapten-specific CD8+ T cell response, suggesting that cell wall components contribute to the immunomodulatory effect of L. casei. This study provides the first evidence that oral administration of L. casei can reduce antigen-specific skin inflammation by controlling the size of the CD8+ effector pool.

Animals↗
PubMed2003

Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation.

To elucidate the role of CD4+CD25+ regulatory T cells in oral tolerance, we used the model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB), which is mediated by CD8+ Tc1 effector cells independently of CD4+ T-cell help. Conversely to normal mice, invariant chain knock-out (KO) (Ii degrees / degrees ) mice, which are deficient in CD4+ T cells, cannot be orally tolerized and develop a chronic hapten-specific CHS response. Transfer of naive CD4+ T cells before hapten gavage into Ii degrees / degrees mice restores oral tolerance by a mechanism independent of interleukin-10 (IL-10) production by CD4+ T cells. That naturally occurring CD4+CD25+ T cells are critical for oral tolerance induction is demonstrated by the finding that (1) transfer of CD4+CD25+ but not CD4+CD25- T cells into Ii degrees / degrees recipients completely prevents the CHS response and skin infiltration by CD8+ T cells, by blocking development of hapten-specific CD8+ T cells; (2) in vivo depletion of CD4+CD25+ cells by antibody treatment in normal mice impairs oral tolerance; and (3) CD4+CD25+ T cells inhibit hapten-specific CD8+ T-cell proliferation and interferon gamma (IFN gamma) production, in vitro. These data show that naturally occurring CD4+CD25+ T cells are instrumental for orally induced tolerance and are key actors for the control of antigen-specific CD8+ T-cell effectors mediating skin inflammation.

Administration, Oral↗
PubMedDate not supplied

CD4+CD25+ T cells as key regulators of immune responses.

Discredited a few years ago, active suppression is now commonly considered as a key mechanism avoiding auto-reactivity and development of potentially harmful immune responses, and in some circumstances, as an obstacle to successful vaccination. A large quantity of literature identifies naturally occurring CD4+CD25+ T cells as key suppressor cells involved in the control of many pathophysiological diseases. Manipulation of these cells and control of their function offers new perspectives for the treatment of auto-immune and inflammatory diseases and enhancement of vaccine efficacy. Such clinical interventions require a better understanding of the conditions of expansion/activation of CD4+CD25+ T cells and deciphering of their mechanism of suppression, which remains incomplete and sometimes controversial.

Animals↗
PubMedDate not supplied

The role of CD4+ and CD8+ T cells in contact hypersensitivity and allergic contact dermatitis.

Allergic contact dermatitis (ACD) and contact hypersensitivity (CHS) are delayed-type hypersensitivity reactions which are mediated by hapten specific T cells. During the sensitisation phases, both CD4+ and CD8+ T cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells. Subsequent hapten skin painting induces the recruitment of T cells at the site of challenge which induces inflammatory signals and apoptosis of epidermal cells, leading to the development of a skin inflammatory infiltrate and of clinical symptoms. There have been major controversies on the respective roles of CD4+ and CD8+ T cells in the development of the CHS inflammatory reaction. Experimental studies from the last 10 years have demonstrated that, in normal CHS responses to strong haptens, CD8+ type 1 T cells are effector cells of CHS while CD4+ T cells are endowed with down-regulatory functions. The latter may correspond to the recently described CD4+ CD25+ regulatory T cell population. However, in some instances, especially those where there is a deficient CD8 T cell pool, CD4+ T cells can be effector cells of CHS. Ongoing studies will have to confirm that the pathophysiology of human ACD is similar to the mouse CHS and that the CHS response to weak haptens, the most frequently involved in human ACD, is similar to that reported for strong haptens.

CD4-Positive T-Lymphocytes↗
PubMedDate not supplied

Allergic contact dermatitis.

Contact dermatitis is an inflammatory skin condition induced by exposure to an environmental agent. Eczema and dermatitis are used synonymously to denote a polymorphous pattern of skin inflammation characterized at least in its acute phase by erythema, vesiculation and pruritus. Substances responsible for contact dermatitis after single or multiple exposures are non protein chemicals, i.e. haptens, that induce skin inflammation through activation of innate skin immunity (irritant contact dermatitis) or both innate and acquired specific immunity (allergic contact dermatitis). The present review will focus on allergic contact dermatitis, a delayed-type hypersensitivity reaction, which is mediated by hapten-specific T cells. Recent advances in the pathophysiology of ACD have shown that the occurrence of ACD, as well as its magnitude and duration, is controlled by the opposite functions of CD8 effector T cells and CD4 regulatory T cells. From these studies ACD can be considered as a breakdown of cutaneous immune tolerance to haptens.

Dermatitis, Allergic Contact↗