In the early phase of leishmaniasis three types of potential antigen-presenting cells, including epidermal Langerhans cells (LC), dermal dendritic cells (DC) and inflammatory DC, are localized at the site of infection. Therefore, it has been a central question which cell type is responsible for the initiation of a protective immune response. In the early stage of an antiLeishmania immune response, detectable Leishmania major antigen was localized in the paracortex of the draining lymph nodes (LN

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The mammalian presenilin (PS) proteins mediate the posttranslational cleavage of several protein substrates, including amyloid precursor protein, Notch family members, and CD44, but they have also been suggested to function in diverse cellular processes, including calcium-dependent signaling and apoptosis. We carried out an integrative computational study of multiple genomic datasets, including RNA expression, protein interaction, and pathway analyses, which implicated PS proteins in Toll

Lymphotoxin (LT)α in combination with LTβ forms membrane‐bound heterotrimeric complexes with a crucial function in lymph node (LN) organogenesis and correct morphogenesis of secondary lymphoid tissue. To study the role of membrane LT (mLT) in lymphoid tissue organogenesis we generated an LTβ‐deficient mouse strain on a pure genetic C57BL/6 background (B6.LTβ–/–) and compared it to a unique series of LTα‐, TNF‐ and TNF/LTα‐gene‐targeted mice on an identical genetic background (B6.LTα–/–, B6.TNF–/– and B6 TNF/LTα–/–). B6.LTβ–/– mice lacked peripheral LN with the exception of mesenteric LN, and displayed a disturbed micro‐architecture of the spleen, although less profoundly than LTα‐ or TNF/LTα‐deficient mice. Radiation bone marrow chimeras (B6.WT→B6.LTβ–/–) developed Peyer's patch (PP)‐like lymphoid aggregates in the intestinal wall indicating a possible role for soluble LTα3 in the formation of the PP anlage. After infection with Leishmania major, B6.LTβ–/– mice developed a fatal disseminating leishmaniasis resulting in death after 8 to 14 weeks, despite the natural resistance of the C57BL/6 genetic background (B6.WT) mice to the parasite. Both, the cellular and the humoral anti‐L. major immune responses were delayed and ineffective. However, the expression pattern of the key cytokines IFN‐γ and IL‐12 were comparable in B6.WT and B6.LTβ–/– mice. Infection of radiation bone marrow chimeras showed that it is the LTβ‐dependent presence of lymphoid tissue and not the expression of mLT itself that renders mice resistant to leishmaniasis.

The type IA topoisomerases have been implicated in the repair of dsDNA breaks by homologous recombination and in the resolution of stalled or damaged DNA replication forks; thus, these proteins play important roles in the maintenance of genomic stability. We studied the functions of one of the two mammalian type IA enzymes, Top3␤, using murine embryonic fibroblasts (MEFs) derived from top3␤ ؊/؊ embryos. top3␤ ؊/؊ MEFs proliferated more slowly than TOP3␤ ؉/؉ control MEFs, demonstrated increased sensitivity to DNA-damaging agents such as ionizing and UV radiation, and had increased DNA double-strand breaks as manifested by increased ␥-H2-AX phosphorylation. However, incomplete enforcement of the G1-S cell cycle checkpoint was observed in top3␤ ؊/؊ MEFs. Notably, ataxia-telangiectasia, mutated (ATM)/ATM and Rad3-related (ATR)-dependent substrate phosphorylation after UV-B and ionizing radiation was impaired in top3␤ ؊/؊ versus TOP3␤ ؉/؉ control MEFs, and impaired up-regulation of total and Ser-18-phosphorylated p53 was observed in top3␤ ؊/؊ cells. Taken together, these results suggest an unanticipated role for Top3␤ beyond DNA repair in the activation of cellular responses to DNA damage.cell cycle checkpoint ͉ DNA repair ͉ radiation sensitivity

Monomorphic MHC class II determinants are attractive targets for immunomodulation. HLA-DR ligation on antigen-presenting cells (APCs) can dramatically alter their function or induce cell death. In monocytes, HLA-DR triggering diminishes their capacity to stimulate T cell proliferation. To further investigate this monocyte-dependent T cell inhibition, we activated human T cells +/- HLA-DR triggering on APCs and tested whether this can induce T cell anergy. Only anti-HLA-DR, but not anti-proliferative control agent anti-CD45, could modulate monocytes in primary cultures with stimulated T cells, so that T cells were hyporesponsive during re-stimulation. Cell separation studies demonstrated that HLA-DR ligation on monocytes is sufficient for mediating T cell anergy. Secretion of monokines was severely reduced after primary culture. Monocytes anergized independently of soluble factors. Extracellular signal-regulated kinase (ERK) phosphorylation occurred early with anti-HLA-DR, but late with anti-CD45 antibody. However, ERK inhibition did not reverse the T cell-anergizing potential of HLA-DR-ligated monocytes implicating other signaling pathways involved in tolerance induction. When analyzing the anergized T cells, they were refractory to exogenous IL-2 and characterized by defective secretion of various cytokines. Expression of CD25, CD28, intracellular CD3zeta and CTLA-4 was reduced. The hyporesponsive T cells up-regulated cell-cycle inhibitors p27(kip1) and p21(cip1) in correlation with human T cell anergy. In contrast, caspase-3 and -8, known to contribute to T cell proliferation, were equally decreased in anti-HLA-DR- and anti-CD45-inhibited cultures. In summary, anti-HLA-DR treatment can generate tolerogenic monocytes transmitting T cell anergy that may be exploited for future immunomodulatory strategies to treat immune-mediated disease states.