No abstract

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.

No abstract