Dendritic cells (DCs) are professional APCs involved in the initiation of both immunity and immunological tolerance. In autoimmune diseases or graft rejections, most reactive lymphocytes are effector/memory cells. It is believed that memory T cells are more resistant to tolerance induction than naive lymphocytes; however, studies on mechanisms for their efficient tolerization are still scarce. In this study, we generated human monocyte-derived DCs by culture with GM-CSF and IL-4 (control DCs), as well as tolerogenic DCs (tDCs) by adding IL-10, IL-10/TGF-β1, or IL-10/IL-6. Cells were maturated with TNF-α/PGE2. Compared with control DCs, tDCs had similar expression of HLA-DR, CD80, and CD86, lower expression of CD40, higher levels of macrophage markers, enhanced endocytic ability, increased secretion of IL-6, IL-10 (only tDCs generated with IL-10 and tDCs generated with IL-10/IL-6), and PGE2, and lower secretion of IL-12 and IL-23. In vitro, tDCs had the capacity to induce anergy in tetanus toxoid-specific memory CD4+ T cells, whereas the proliferative response to an unrelated Ag was intact. Anergy could be reverted upon exposure to IL-2. tDC-primed T cells have low suppressive ability. Nevertheless, the generation of both anergic and regulatory T cells was more efficient with tDCs generated with IL-10/TGF-β1. Microarray-based gene expression profiling reflected modulated expression of several transcripts in tDCs. Surface CLIP–HLA-DR complexes and intracellular thrombospondin-1 were increased in the three tDCs. CD39 was highly expressed only in tDC-TGF, which correlated with increased adenosine production. We propose that these molecules, together with IL-10 and prostanoids, are key factors to induce Ag-specific tolerance in memory T cells.

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Two major subsets of human Mo are identified based on CD14 and CD16 expression: the classical CD16(-) Mo and the minor CD14(+)CD16(+) Mo. In vitro studies suggested distinct function and differentiation potential for each cell population. However, the in vivo relevance of these findings remains unclear. To evaluate the development and function of human Mo in an in vivo model, we transferred both Mo subpopulations into the peritoneum of immunocompromised mice in homeostatic or inflammatory conditions. Inflammation was induced with soluble LPS or particulate zymosan. CD16(+) were more phagocytic and produced higher amounts of TNF and IL-6 than CD16(-) Mo early after transfer with zymosan. They also produced higher levels of β2-defensin in any condition evaluated, which could represent a new marker for this subpopulation. In contrast, differentiating CD16(-) Mo (24 h after transfer) acquired greater APC capacity in LPS-induced peritonitis, whereas none of the Mo subsets attained this ability with zymosan. CX(3)CL1 supported the survival of both Mo subsets in vivo. Similar Mo subpopulations were present in human peritonitis. These results support the idea of specialized roles of the Mo subset, where CD16(+) might act in an immediate innate immune response, whereas CD16(-) could have a major role as APCs.

Prolactin, a 23-kDa peptide hormone, is produced by the anterior pituitary gland and extrapituitary sites including the immune cells. Prolactin (PRL) participates in innate and adaptive immune response. PRL stimulates the immune cells by binding to receptor (PRL-R). Binding of PRL to its receptor activates the Janus kinase-signal transducer (JAK-STAT). Activation of these cascades results in endpoints such as immunoestimulator and immunosupressor action. Prolactin belongs to the network of immune-neuroendocrine interaction. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE), and new evidence has confirmed a significant correlation between serum PRL levels and disease activity. PRL participates in activation of SLE during pregnancy and in pathogenesis of lupus nephritis, neuropsychiatric, serosal, hematologic, articular, and cutaneous involvement. Hyperprolactinemia was associated with increase IgG concentrations, anti-DNA antibodies, immune complex, glomerulonephritis, and accelerated mortality in murine lupus. Bromocriptine, a dopamine analog that suppresses PRL secretion, was associated with decreased lupus activity, prolonged lifespan, and restoration of immune competence in experimental model. In clinical trials, bromocriptine and derivative drugs showed beneficial therapeutic effect in treating human lupus, including pregnancy. Taken together, clinical and experimental results leave little doubt that PRL indeed contributes to the pathogenesis and clinical expression of SLE.

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