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...

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Early studies described CD69 as a leukocyte activation marker, and suggested its involvement in the activation of different leukocyte subsets as well as in the pathogenesis of chronic inflammation. However, recent investigations have showed that CD69 knockout mice exhibit an enhanced susceptibility to different inflammatory diseases, mainly those mediated by Th17 lymphocytes. The recent discovery of a ligand for CD69 expressed on Dendritic cells, Galectin-1, has confirmed the immunoregulatory role of CD69 mainly by the inhibition of Th17 differentiation and function in mice and humans. In this regard, the expression of CD69, both in Th17 lymphocytes and by a subset of regulatory T cells, has an important role in the control of the immune response and the inflammatory phenomenon. Therefore, different evidences indicate that CD69 exerts a complex immuno-regulatory role in humans, and that it could be considered as target molecule for the therapy of immune-mediated diseases. Keywords CD69; Inflammatory diseases; Treg lymphocytes; Th17 lymphocytes, Immuno-regulation CD69 IS AN EARLY ACTIVATION ANTIGEN OF IMMUNE CELLSCD69 is a type II C-lectin membrane receptor with a scarce expression in resting lymphocytes that is rapidly induced upon cell activation. CD69 gene maps at human chromosome 12, and behaves as an early activation gene that contains responsive elements for the transcription factors NF-κB, ERG-1 and AP-1 (Fig. 1A). Early in vitro data as well as the prominent expression of CD69 in chronic inflammatory cell infiltrates suggested that this receptor has an important role in the activation of leukocytes, exerting a proinflammatory effect. Recent studies in CD69-deficient mice indicate that this molecule Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts exerts a complex and interesting role in the modulation of the immune response and the inflammatory phenomenon [1]. However, these studies have been controversial for a while since two different models of CD69 deficient mice have been described with opposite effects in the development of T-cell independent arthritis and Th2-dependent asthma. Murata et al. 2003 [2] described a CD69 knockout mice that were protected towards arthritis induced by anti-type II collagen antibodies whereas Lamana et al. 2006 [3] revisited the same disease model with an independent CD69-deficient mice and found that the lack of CD69 did not inhibits joint inflammation. Lamana et al. used monoclonal antibodies against CD69 in wild type mice, that downregulates the expression of the molecule in the membrane, to bypass putative different genetic alterations in the process of generation of these two different animal models. These investigations confirmed that the lack of CD69 do not protects the mice towards the T-independent model of neutrophil-mediated arthritis.Regarding the role of CD69 in asthma, Miki-Hosokawa et al. 2009 described that the reduced migration of Th2 cells accounts for the inhibition of lung inflammation in a model of CD69 null mice [4]...

Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this concept has been challenged by recent reports demonstrating that both CD8- and CD8+ DCs, considered in mice as archetypes of myeloid and lymphoid DCs respectively, can be generated from either lymphoid or myeloid progenitors. The issue of DC physiological derivation therefore remains an open question. Here we report the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs---including CD8- and CD8+ DCs, as well as the B220+ DC subset---but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.

Differentiation of T helper lymphocyte subsets is crucial for immune and inflammatory responses. In addition to the two classical T helper cell subsets (Th1 and Th2), a third T-lymphocyte subpopulation, designated Th17, characterized by the synthesis of interleukin 17A (IL-17A), IL-17F, and IL-22, has emerged as an independent differentiation pathway (9). Differentiation toward each Th subset is regulated by a variety of molecules, including cytokines and transcription factors. The key transcription factors that drive the differentiation of the Th1 and Th2 lineages are, respectively, T-bet and GATA-3, while the differentiation of Th17 cells is directed by retinoic acid-related orphan receptor ␥t (ROR␥t) (12). Th17 differentiation, moreover, is regulated by the balance of Stat3/Stat5 activation; Stat3 is necessary for Th17 differentiation, whereas the transcription factor Stat5 negatively regulates the development of these cells (1). The key cytokines involved in Th17 cell differentiation are transforming growth factor ␤ (TGF-␤) and IL-6 (3, 33). Another important cytokine for Th17 biology is IL-23. Although Th17 cells can arise in the absence of IL-23, the cytokine is required for their maintenance and survival (29, 33) and for their pathogenicity (20).Dysregulated activation of T helper subpopulations is associated with immune pathogenesis (21). Th1 cells are clearly involved in autoimmune and inflammatory disorders mediated by the cellular immune response, and Th2 cells are involved in antibody-mediated allergic and inflammatory conditions (24).Recent evidence indicates that Th17 cells also exert a pathogenic effect in several autoimmune and hypersensitivity reactions. Indeed, a number of immune pathologies previously thought to be related to uncontrolled activation of Th1 or Th2 populations now appear to be related, at least in part, to Th17 cell differentiation. For example, involvement of Th17 lymphocytes has been reported in collagen-induced arthritis (CIA), experimental autoimmune encephalomyelitis (EAE), experimental autoimmune myocarditis (EAM), contact hypersensitivity (CHS), and airway hyperresponsiveness (AHR) (11,13,18,22,23,30).We previously found that CD69 ϩ T cells are localized at sites of chronic inflammation and that these lymphocytes seem to be able to downregulate the inflammatory process. Although antigen-dependent T-cell activation and proliferation do not appear to be altered in CD69-deficient lymphocytes (16), CD69 knockout (CD69 KO) mice develop an exacerbated form of CIA characterized by diminished local synthesis of TGF-␤ (26). These and other studies (5) suggest that CD69 is a negative regulator of the immune response, in part through modulation of local levels of TGF-␤. Here, we explore the role of CD69 in the differentiation of T helper lineages. Our results show that, while Th1 and Th2 differentiation remain unchanged in CD69-deficient mice, lymphocytes from these animals show an enhanced potential to differentiate toward Th17 cells both in vitro and in vivo. Biochemical and funct...