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Every person harbors a population of potentially self-reactive lymphocytes controlled by tightly balanced tolerance mechanisms. Failures in this balance evoke immune activation and autoimmunity. In this study, we investigated the contribution of self-reactive CD8+ T lymphocytes to chronic pulmonary inflammation and a possible role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes downregulated the expression of effector molecules, those located in the spleen appeared to be partly Ag-experienced and displayed a memory-like phenotype. Because ex vivo-reisolated self-reactive CD8+ T cells were very well capable of responding to the Ag in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung. Notably, CD8+ T cell tolerance established in the lung depends only partially on the function of nTregs, because self-reactive CD8+ T cells underwent only biased activation and did not acquire effector function after nTreg depletion. However, although transient ablation of nTregs did not expand the population of self-reactive CD8+ T cells or exacerbate the disease, it provoked rapid accumulation of activated CD103+CD62Llo Tregs in bronchial lymph nodes, a finding suggesting an adaptive phenotypic switch in the nTreg population that acts in concert with other yet-undefined mechanisms to prevent the detrimental activation of self-reactive CD8+ T cells.

Additional file 1: Figure S1. A) Schematic illustration of functionalized multi shell calcium phosphate (CaP) nanoparticles. B) C57BL/6 mice were chronically infected with FV (>6 weeks) and therapeutically vaccinated either with PBS or functionalized CaP nanoparticles. 7 or 14 days post vaccination (d.p.v.), mice were sacrificed for analyzes. C) The percentage of CD4+ CD43+ and CD8+ CD43+ effector cells is shown. D) Frequency of granzyme B (GzmB) expressing CD43+ CD8+ T cells and CD43+ CD8+ FV-specific T cells identified by tetramer staining recognizing the H-2Db-restricted FV gag epitope is depicted. E) 7 and 14 d.p.v., mice were sacrificed, and infectious centers in the spleen were determined. The figure summarizes the results of 3 independent experiments. Statistical analysis was performed by studentâ s t-test. *p

CD4⁺CD25⁺ regulatory T cells (Trₑg cells) control immune responsiveness to a large variety of antigens. The isolation and therapeutic manipulation of Trₑg cells requires the use of reliable surface receptors that are selectively up-regulated in Trₑg cells. On the basis of global gene expression studies, we identified neuropilin-1 (Nrp1) as a specific surface marker for CD4⁺CD25⁺ Trₑg cells. Nrp1, a receptor involved in axon guidance, angiogenesis, and the activation of T cells, is constitutively expressed on the surface of CD4⁺CD25⁺ Trₑg cells independently of their activation status. In contrast, Nrp1 expression is down-regulated in naive CD4⁺CD25⁺ T cells after TCR stimulation. Furthermore, CD4⁺Nrp1hⁱgh T cells express high levels of Foxp3 and suppress CD4⁺CD25⁺ T cells. Thus, Nrp1 constitutes a useful surface marker to distinguish Trₑg cells from both naive and recently activated CD4⁺CD25⁺ nonregulatory T cells. © 2004 Wiley-VCH Verlag GmbH & Co.

Background and Aims: Impairment of cell-mediated immunity has long been recognized in classical Hodgkin’s lymphoma (cHL), but it is still under discussion whether the ineffective immune clearance of Hodgkin/ Reed-Sternberg (H/R-S) cells is exclusively resulting from the immunosuppressive environment at the tumor site or might be due to a primary T cell defect. Therefore, we applied a microarray approach in order to analyze circulating T lymphocytes for specific dysregulation. Material and Methods: CD3+ T cells isolated from peripheral blood samples of untreated patients with cHL were analyzed for their gene expression profile in comparison to 2 control groups consisting of healthy donors and patients with sarcoidosis by applying Affymetrix HG-U95Av2 GeneChip. Fold change values of normalized differentially expressed genes (p Results:Among more than 12,500 genes 541 transcripts were detected as differentially expressed (p99%; ANOVA analysis). A hierarchical clustering identified within 541 selected transcripts specific expression profiles clearly discriminating between cHL and the control groups (Figure 1.): The identified transcripts fell into several functional classes of genes important in cell cycle regulation (i.e., cyclin A/B1, Cdc2), translational control (i.e., RPL23, LOXL1, ARAF1), intercellular communication/receptor (i.e., CXCR3, CXCR5), and most importantly immune response (i.e., cathepsin C, LTß, MIP1ß, SAP). Conclusions: The molecular study identified that circulating T lymphocytes of cHL seem to be globally affected in cell cycle transition, proliferation and Th1/Th2 balance with induction of immune regulatory genes. Altogether these results are arguing for a primary cellular defect contributing to an ineffective immune clearance of H/R-S cells. Figure 1. Distribution of the 541 differentially expressed genes discriminating between cHL and control groups CCG, Cytokines/chemokines, growth factors and receptors; BM, bioynthesis and metabolism; adhesion and motility; HLA, HLA and heat shock proteins; CIT, Calcium and ion channel binding and other transporters; AP, apoptosis and proteolytic systems; MP, membrane proteins and other proteins; TR, transcriptional regulation; IR, other immune related genes; CP, cell proliferation and regulation genes; ES, enzymes and other signal molecules; MISC, miscellaneous. Figure 1. Distribution of the 541 differentially expressed genes discriminating between cHL and control groups . / CCG, Cytokines/chemokines, growth factors and receptors; BM, bioynthesis and metabolism; adhesion and motility; HLA, HLA and heat shock proteins; CIT, Calcium and ion channel binding and other transporters; AP, apoptosis and proteolytic systems; MP, membrane proteins and other proteins; TR, transcriptional regulation; IR, other immune related genes; CP, cell proliferation and regulation genes; ES, enzymes and other signal molecules; MISC, miscellaneous.