We describe a new B220 ؉ subpopulation of immaturelike dendritic cells (B220 ؉ DCs) with low levels of expression of major histocompatibility complex (MHC) and costimulatory molecules and markedly reduced T-cell stimulatory potential, located in the thymus, bone marrow, spleen, and lymph nodes. B220 ؉ DCs display ultrastructural characteristics resembling those of human plasmacytoid cells and accordingly produce interferon-␣ after virus stimulation. B220 ؉ DCs acquired a strong antigen-presenting cell capacity on incubation with CpG oligodeoxynucleotides, concomitant with a remarkable up-regulation of MHC and costimulatory molecules and the production of interleukin-12 (IL-12) and IL-10. Importantly, our data suggest that nonstimulated B220 ؉ DCs represent a subset of physiological tolerogenic DCs endowed with the capacity to induce a nonanergic state of T-cell unresponsiveness, involving the differentiation of T regulatory cells capable of suppressing antigen-specific T-cell proliferation. In conclusion, our data support the hypothesis that B220 ؉ DCs represent a lymphoid organ subset of immature DCs with a dual role in the immune system-exerting a tolerogenic function in steady state but differentiating on microbial stimulation into potent antigen-presenting cells with type 1 interferon production capacity. IntroductionMaintenance of immunologic self-tolerance is an essential process directed at preventing harmful autoimmune diseases caused by autoreactive T cells capable of responding to self-antigens. Avoidance of pathologic reactivity of self-reactive T cells may occur as a consequence of T-cell deletion, T-cell unresponsiveness, or, in some instances, T helper cell type 2 (TH2) skewing (reviewed in Hackstein et al 1 ). Deletion of autoreactive T-cell clones, resulting in T-cell-negative selection, takes place essentially in the thymus under the control of thymic dendritic cells (DCs) and epithelial cells (reviewed in Ardavín 2 ). In contrast, the molecular mechanisms controlling T-cell unresponsiveness or anergy, which is the basis of peripheral tolerance, are not fully understood. However, increasing evidence supports that T regulatory (T reg ) cells play an essential role in the control of autoreactive T-cell clones and, therefore, in the maintenance of T-cell peripheral tolerance because of their capacity to suppress antigen-specific T-cell responses (reviewed in Roncarolo and Levings 3 ). Interestingly immature DCs have been demonstrated to participate in the differentiation of T reg cells (reviewed in Jonuleit et al 4 ). In this sense, human and mouse interleukin-10 (IL-10)-treated immature DCs have been reported to induce antigen-specific T-cell anergy. [5][6][7][8][9] In addition, in vitrogenerated human immature DCs have been demonstrated to induce the differentiation of T reg cells in vitro and in vivo. 9,10 Therefore, on the basis of these data, the tolerogenic potential of DCs has been proposed to be correlated with an immature DC state. 1 On the other hand, DC-mediated induction of murine T-ce...
The p42 and p44 mitogen-activated protein kinases (MAPKs), also called Erk2 and Erk1, respectively, have been implicated in proliferation as well as in differentiation programs. The specific role of the p44 MAPK isoform in the whole animal was evaluated by generation of p44 MAPK-deficient mice by homologous recombination in embryonic stem cells. The p44 MAPK-/- mice were viable, fertile, and of normal size. Thus, p44 MAPK is apparently dispensable and p42 MAPK (Erk2) may compensate for its loss. However, in p44 MAPK-/- mice, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CD3high). In p44 MAPK-/- thymocytes, proliferation in response to activation with a monoclonal antibody to the T cell receptor in the presence of phorbol myristate acetate was severely reduced even though activation of p42 MAPK was more sustained in these cells. The p44 MAPK apparently has a specific role in thymocyte development.
We have recently reported that the sublingual (s.l.) mucosa is an efficient site for inducing systemic and mucosal immune responses. In this study, the potential of s.l. immunization to induce remote Ab responses and CD8+ cytotoxic responses in the female genital tract was examined in mice by using a nonreplicating Ag, OVA, and cholera toxin (CT) as an adjuvant. Sublingual administration of OVA and CT induced Ag-specific IgA and IgG Abs in blood and in cervicovaginal secretions. These responses were associated with large numbers of IgA Ab-secreting cells (ASCs) in the genital mucosa. Genital ASC responses were similar in magnitude and isotype distribution after s.l., intranasal, or vaginal immunization and were superior to those seen after intragastric immunization. Genital, but not blood or spleen, IgA ASC responses were inhibited by treatment with anti-CCL28 Abs, suggesting that the chemokine CCL28 plays a major role in the migration of IgA ASC progenitors to the reproductive tract mucosa. Furthermore, s.l. immunization with OVA induced OVA-specific effector CD8+ cytolytic T cells in the genital mucosa, and these responses required coadministration of the CT adjuvant. Furthermore, s.l. administration of human papillomavirus virus-like particles with or without the CT adjuvant conferred protection against genital challenge with human papillomavirus pseudovirions. Taken together, these findings underscore the potential of s.l. immunization as an efficient vaccination strategy for inducing genital immune responses and should impact on the development of vaccines against sexually transmitted diseases.
Dendritic cells (DC) are highly efficient antigen-presenting cells (APC) that have an essential function in the development of immune responses against microbial pathogens and tumors. Although during the past few years our understanding of DC biology has remarkably increased, a precise characterization of the different DC subpopulations remains to be achieved with regard to their phenotype and lineage relationships. In this report, we have extensively studied the DC subpopulations present in the thymus, spleen, Peyer’s patches, lymph nodes (LN) and skin of the mouse. Thymus DC and 60% spleen DC have a lymphoid DC phenotype, ie, CD8+DEC-205high Mac-1low, whereas 40% spleen DC have a myeloid DC phenotype, ie, CD8−DEC-205low Mac-1high. Both CD8+and CD8− DC are leukocyte function-associated antigen-1 (LFA-1)high and highly adherent. Within Peyer’s patches the majority of DC correspond to the CD8+DEC-205high Mac-1lowlymphoid category. In the LN, together with CD8+ and CD8− DC, an additional nonadherent CD8intLFA-1int subpopulation with lymphoid DC characteristics is described. Finally, in the skin both epidermal Langerhans cells (LC) and dermal DC are CD8−DEC-205high Mac-1high , and do not express LFA-1. Interestingly, LC migration experiments indicate that LC underwent the upregulation of CD8 and LFA-1 upon migration to the LN, supporting the hypothesis that LC belong to the CD8+ lymphoid lineage.
Although dendritic cells (DCs) regulate immune responses, they exhibit functional heterogeneity depending on their anatomical location. We examined the functional properties of intestinal DCs after oral administration of cholera toxin (CT), the most potent mucosal adjuvant. Two CD11c+ DC subsets were identified both in Peyer’s patches and mesenteric lymph nodes (MLN) based on the expression of CD8α (CD8+ and CD8− DCs, respectively). A third subset of CD11c+CD8int was found exclusively in MLN. Feeding mice with CT induced a rapid and transient mobilization of a new CD11c+CD8− DC subset near the intestinal epithelium. This recruitment was associated with an increased production of the chemokine CCL20 in the small intestine and was followed by a massive accumulation of CD8int DCs in MLN. MLN DCs from CT-treated mice were more potent activators of naive T cells than DCs from control mice and induced a Th2 response. This increase in immunostimulating properties was accounted for by CD8int and CD8− DCs, whereas CD8+ DCs remained insensitive to CT treatment. Consistently, the CD8int and CD8− subsets expressed higher levels of costimulatory molecules than CD8+ and corresponding control DCs. Adoptive transfer experiments showed that these two DC subsets, unlike CD8+ DCs, were able to present Ags orally coadministered with CT in an immunostimulating manner. The ability of CT to mobilize immature DCs in the intestinal epithelium and to promote their emigration and differentiation in draining lymph nodes may explain the exceptional adjuvant properties of this toxin on mucosal immune responses.
Inherent immune suppression represents a major challenge in the treatment of human cancer. The extracellular matrix molecule tenascin-C promotes cancer by multiple mechanisms, yet the roles of tenascin-C in tumor immunity are incompletely understood.Using a 4NQO-induced oral squamous cell carcinoma (OSCC) model with abundant and absent tenascin-C, we demonstrated that tenascin-C enforced an immune suppressive lymphoid stroma via CCL21/CCR7 signaling, leading to increased metastatic tumors. Through TLR4, tenascin-C increased expression of CCR7 in CD11c+ myeloid cells. By inducing CCL21 in lymphatic endothelial cells via integrin and binding to CCL21, tenascin-C immobilized CD11c+ cells in the stroma. Inversion of the lymph node-to-tumor CCL21 gradient, recruitment of T regulatory cells, high expression of anti-inflammatory cytokines and matrisomal components were hallmarks of the tenascin-C-instructed lymphoid stroma. Ablation of tenascin-C or CCR7 blockade inhibited the lymphoid immune suppressive stromal properties, reducing tumor growth, progression and metastasis. Thus, targeting CCR7 could be relevant in human head and neck tumors as high tenascin-C expression and an immune suppressive stroma correlate to poor patient survival.
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