Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

With newly generated ICOS‐ligand (ICOS‐L)‐specific monoclonal antibodies we determined that human Langerhans cells in situ express similar levels of ICOS‐L, CD80, and CD86, compared to immature dendritic cells (DC) derived from monocytes in vitro. Maturation of DC strongly up‐regulated CD80 and CD86 but did not significantly change ICOS‐L levels. On coculture of "naive"CD4+ T cells with mature DC in the presence of superantigen, ICOS was highly up‐regulated on T cells, but played only a secondary role in the CD28‐dominated release of TNF‐α and IFN‐γ , and did not participate in the induction of IL‐2. Cocultures of "effector" CD4+ T cells with mature DC revealed CD28 as the driving force for the secretion of IL‐2, IFN‐γ , IL‐6, and IL‐13, with no apparent contribution of ICOS. In contrast, the release of IL‐10 was differentially regulated. Interaction of ICOS with ICOS‐L strongly promoted IL‐10 secretion, whereas the CD28/B7 pathway acted as a potent attenuator of IL‐10 release. Our data thus indicate a selective regulation of IL‐10 secretion by ICOS on re‐activation of effector T cells with professional antigen‐presenting cells (bearing CD80 and CD86) in lymphoid tissue.

The chronic graft-versus-host (cGvH) reaction is a model of induced lupus caused by alloreactive CD4+ T cells from a Bm-12 mouse in a C57BL/6 recipient. We used this cGvH reaction in C57BL/6 anti-DNA H chain transgenic mice, 56R/B6, to understand the structure, specificity, and origin of the induced autoantibodies (auto-Abs). We found anti-DNA Abs that reacted to several different antigens, such as phosphatidylserine, myelin basic protein, thyroglobulin, histone, insulin, cytochrome C, and β-galactosidase. This polyreactivity was found for Abs from B cells that expressed the 56R H chain transgene with “editor” L chains that did not completely veto autoreactivity. We suggest that such incomplete editing results in polyreactivity and that incompletely edited polyreactive B cells influence the subsequent expression of pathogenic auto-Abs in disease. We also found B cells that coexpress κ and λ L chain. These B cells contributed to the autoimmune response and are possibly in the marginal zone of the spleen.

DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.

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T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.

Our data indicate that fingolimod - apart from trapping lymphocytes in lymph nodes - exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

Summary CD4+ CD45RO+ T cells could mature freshly isolated human plasmacytoid dendritic cells (PDC) in a superantigen‐driven culture in a similar way to recombinant interleukin‐3 (IL‐3). Mature PDC expressed significantly higher levels of inducible costimulator ligand (ICOS‐L), but similar levels of CD80 and CD86, when compared to mature monocyte‐derived DC (moDC). We therefore directly compared the capacities of mature PDC and moDC to activate T cells. A similar T helper type 1 (Th1)/Th2 pattern of cytokines was generated in both systems, but significantly higher levels of IL‐3, IL‐4 and IL‐10 were induced by PDC. In T cells interacting with PDC, the ICOS/ICOS‐L costimulatory pathway played a pre‐eminent role in the generation of IL‐3 and IL‐10, CD28 was central to the induction of IL‐2, and both pathways were equally important for the generation of other cytokines. In cocultures with moDC, the CD28 pathway was dominant over ICOS under all circumstances, except for the ICOS‐mediated release of IL‐10. In general, our data demonstrate an eminent role of ICOS in the interaction of T cells with PDC, and thus modify the current paradigm of CD28 dominance for the costimulation of T cells interacting with professional antigen‐presenting cells. In particular, our data highlight the role of ICOS in the generation of IL‐3, a factor central to the biology of human PDC.