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Virtually all cells require some sort of communication between the outside of the cell and the inside. External events, often the binding of a molecule to a specific receptor on a cell surface, signal the initiation of a complex series of events within the cell. Nowhere is this signalling more evident than in the immune system. In the case of T cells, the cell responds to the presentation of specific antigen with a series of changes collectively called 'activation'. The activation of a T cell apparently begins when the T cell receptor is presented with specific antigen. The T cell receptor is associated with a second molecular complex, called CD3, which is thought to transduce the signal, that is, convert it into biochemical changes within the cell. The nature of such transduction is a major problem for modern biology. Now, however, it has been found that the same molecular complex, the T cell receptor/CD3 complex, or TCR-CD3, may in fact accomplish this transduction differently in different cells. Two different cell lines were used to examine the molecular events following TCR-CD3 stimulation. Both the HPB-ALL cell line and the Jurkat cell line express large quantities of TCR-CD3 on their cell surfaces. However, the Jurkat cell line responds to stimulation with a mobilization of intracellular calcium and the production of inositol phosphate. (Inositol phosphate is another so-called 'second messenger', which is used by many cells to signal the occurrence of specific biochemical events.) When the same stimulation of HPB-ALL is examined, no production of inositol phosphate is observed. Both cells were found to have normal levels of the enzyme calcium-induced phospholipase C, a key enzyme in the transduction process. Therefore, the absence of inositol phosphate production cannot be attributed to the absence or relative lack of this enzyme. In the HPB-ALL cell line, the events occurring on the cell surface are uncoupled from the activation of this enzyme. Similarly, the activity of the enzyme protein kinase C, which signals by adding a phosphate group to proteins, was also uncoupled from the stimulation of the TCR-CD3 complex in the HPB-ALL cells. The results indicate that the same cell surface receptor may operate by stimulating different intracellular events in different cell lines. (Consumer Summary produced by Reliance Medical Information, Inc.)

Quinoline-3-carboxamide compounds (Q compounds) have demonstrated efficacy in treating autoimmune disease in both humans and mice. However, the mode of action of these compounds is poorly understood. Here, we show that preventive treatment with the Q compound paquinimod (ABR-215757) during the first 5 days after induction of experimental autoimmune encephalomyelitis is sufficient to significantly ameliorate disease symptoms. Parallel cell-depletion experiments demonstrated that Ly6Chiinflammatory monocytes play an essential role in this phase. The paquinimod-induced amelioration correlated with reduced priming of antigen-specific CD4+T cells and reduced frequency of IFN-γ– and IL-17–producing cells in draining lymph nodes. Importantly, the treatment did not inhibit T-cell division per se. In mice with established experimental autoimmune encephalomyelitis, the numbers of Ly6ChiCD115+inflammatory monocytes and CD11b+CD11c+dendritic cells (DCs) were reduced in spleen, but not in bone marrow or draining lymph nodes of treated mice. Inflammatory monocyte–derived DCs and CD4+T cells were also reduced in the brain. In contrast, there was no decrease in DC subsets previously shown to be critical for effector CD4+T-cell development in lymph nodes. Taken together, these data indicate that preventive treatment with paquinimod ameliorates experimental autoimmune encephalomyelitis by reducing effector T-cell priming and, on prolonged treatment, displays a selective effect by decreasing distinct subpopulations of splenic CD11b+myeloid cells.

Previous studies have demonstrated that anti-CD40L or anti-B7 requires the presence of CD4CD25regulatory T cells (Treg) to induce antigen specific hyporesponsiveness. Other tolerance strategies involving Treg have shown a dependency on interleukin (IL)-10. The objective of this study was to investigate the role of CD4CD25Treg and IL-10 when treating transplant recipients with cytotoxic T lymphocyte-associated antigen (CTLA)-4 immunoglobulin (Ig), anti-CD40L, and anti-lymphocyte function-associated antigen (LFA)-1.

Members of the transforming growth factor (TGF)-beta family play pivotal roles in the control of differentiation, proliferation and tolerance in peripheral T cells. Recently, they have been implicated in thymic selection, but their role is so far not well characterized. In the present study, we demonstrate that specific thymocyte populations are under the influence of either the TGF-beta and/or Activin pathway, and transduce signals into the nucleus via phosphorylated Smad2 (pSmad2). Thymocytes in the medulla and in the subcapsular zone expressed nuclear translocated pSmad2, a hallmark of active TGF-beta/Activin receptor signaling. When analyzed at the cellular level, the pSmad2(+) cells were confined to the double-negative (DN) and single-positive (SP) subpopulations. Moreover, the most immature DN thymocytes (CD44(+)CD25(-) and CD44(+)CD25(+)) expressed higher levels of pSmad2 compared to the more mature DN. In vitro stimulation demonstrated that pure CD44(+)CD25(-), CD44(+)CD25(+) and CD44(+)CD25(+) thymocytes respond to ActivinA, while the mature CD4(+) and CD8(+) SP thymocytes respond to TGF-beta stimulation measured as enhanced phosphorylation of Smad2. Double staining of pSmad2(+) cells with either the Activin type I receptor, ALK4, or the TGF-beta type I receptor, ALK5, demonstrated that pSmad2(+) DN cells exhibited high levels of immunoreactivity to ALK4 and moderate levels of immunoreactivity to the TGF-beta-responsive ALK5 receptor. In sharp contrast, the SP pSmad2(+) cells were predominately ALK5(+). Collectively, our results demonstrate that early and late thymocytes express pSmad2 in the nuclei in vivo. The functional experiments in vitro suggest that members of the TGF-beta family (TGF-beta or Activin) may play important non-redundant roles during different stages of thymopoiesis.

The pre-Tα (pTα ) gene encodes a protein that forms the pre-TCR together with the newly expressed TCR β chain during a defined stage of early T cell development. The restricted expression of this gene has been suggested to depend on a promoter and an enhancer element containing E boxes, which are potential binding sites for basic helix-loop-helix (bHLH) proteins. We here report that increased expression of E47 and E12 mRNA in CD4^–CD8^–TCR^– thymocytes correlates with the initiation of pTα  transcription. Furthermore, electrophoretic mobility shift assays suggested that E47 binds directly to both the pTα  promoter and enhancer in vitro. Ectopic expression of E47 in non-lymphoid HeLa cells resultedin a dose- and template-dependent activation of these control elements. In addition to this, ectopic expression of E47 in combination with the ets-protein Pu.1 and / or the Pu.1-interacting protein(Pip-1), resulted in a synergistic effect on the activity of the pTα  control elements. Thus, we suggest that E47, Pu.1 and Pip-1 are directly involved in the regulation of pTα expression inearly T cell development.

CD4⁺CD25⁺ T cells have been shown to inhibit experimentally induced organ-specific autoimmune disease and depletion of these regulatory T cells from normal mice results in development of such conditions. Furthermore, CD4⁺CD25⁺ T cells suppress the IL-2 production and thereby the proliferation of polyclonally activated CD4⁺CD25^– T cells in vitro. The suppression in vitro is independent of secreted factors but requires interactions between CD4⁺CD25^– and CD4⁺CD25⁺ T cells and antigen-presenting cells (APC). We have now further investigated the function of CD4⁺CD25⁺ T cells in vitro and have focused on their interactions with APC. We found that CD4⁺CD25⁺ T cells down-regulated the expression of the co-stimulatory molecules CD80 and CD86 on dendritic cells. The steady-state level of CD80 mRNA was also decreased, while the steady-state level of CD86 mRNA was not, suggesting that distinct mechanisms regulate the expression of these molecules. The down-regulation occurred even in the presence of stimuli that would normally increase the expression of CD80 and CD86 molecules. Thus, down-regulation of co-stimulatory molecules may be an additional effector function of these regulatory T cells.

The proportion of CD4⁻ CD8⁻ double-negative (DN) α β T cells is increased both in the thymus and in peripheral lymphoid organs of TCR α chain-transgenic mice. In this report we have characterized this T cell population to elucidate its relationship to α β and γ δ T cells. We show that the transgenic DN cells are phenotypically similar to γ δ T cells but distinct from DN NK T cells. The precursors of DN cells have neither rearranged endogenous TCRα genes nor been negatively selected by the Mls^a antigen, suggesting that they originate from a differentiation stage before the onset of TCR α chain rearrangements and CD4/CD8 gene expression. Neither in-frame VδDδJδ nor VγJγ rearrangements are over-represented in this population. However, since peripheral γ δ T cells with functional TCRβ gene rearrangements have been depleted in the transgenics, we propose that the transgenic DN population, at least partially, originates from the precursors of those cells. The present data lend support to the view that maturation signals to γ δ lineage-committed precursors can be delivered via TCR α β heterodimers.

Most T cells in a normal non-immunized individual are in a resting state. However, a small proportion of splenic T cells are large activated cells both in specific pathogen-free and antigen-free mice. To further elucidate the effector functions associated with these "naturally" activated CD4⁺ T cells, we have characterized the expression of various membrane markers, cytokine production and T helper activity by these cells. We show that naturally activated CD4⁺ T cells express activation markers and contain tenfold higher proportions of cells producing IL-4, IL-10 and IFN-γ as compared to small CD4⁺ T cells. Despite the high proportion of IFN-γ producers, naturally activated CD4⁺ T cells still induce B cell proliferation and differentiation. These results are discussed in the context of normal physiological autoreactivity.

By promoting noncanonical NF-κB signaling, SMAC mimetics can reprogram CD4+T helper cell differentiation and curb autoimmunity.

We have investigated the role of the Ca2+-binding protein S100A9 on tumor growth in prostate cancer and T-cell lymphoma models. We found that the expression of, S100A9 and its interaction with Toll-like receptor 4 (TLR4) is critical for tumor growth in these settings.

Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9.