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Introduction: Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. The transcriptional activator CREB was previously shown to stabilize Foxp3 expression in vitro. Methods: To elucidate the function of CREB in regulatory [for full text, please go to the a.m. URL]

Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy., The activity of immune cells can be regulated by the microbiome. Here, the authors show that the fatty acids pentanoate and butyrate—normally released by the microbiome—increase the anti-tumour activity of cytotoxic T lymphocytes and chimeric antigen receptor T cells through metabolic and epigenetic reprogramming.

Background: In the last years miRNAs have emerged as critical regulators of innate and adaptive immune responses and an altered expression or function is associated with several inflammatory and autoimmune diseases. Therefore miRNAs are also believed to promote inflammatory processes within the inflamed[for full text, please go to the a.m. URL], 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

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Figure S1. Expression of ANXA3 using RT-PCR: delta Ct values (relative expression values related to RPL) in controls, active systemic or polyarticular disease and inactive disease (***p

Figure S1. Bronchial hyperresponsiveness in C57BL6 mice in LPS-induced acute lung injury. Mice were instilled with 50 μL of LPS (4 mg/kg) or saline (controls) on day 0 and were mechanically ventilated 1, 4 or 10 days after ARDS induction. Mice of basal group were mechanical ventilated without prior i.t. instillation. (A-D) Lung function parameters resistance (Rrs), elastance (Ers), tissue damping (G) and tissue elastance (H) on day 1, 4 and 10 after ARDS-induction following acetylcholine stimulation (controls n = 4, ARDS group n = 6 per time point, means ± SEM). * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (PDF 311 kb)

Figure S2. Bronchial hyperresponsiveness in RAG2−/− and wildtype mice in LPS-induced acute lung injury. Mice were instilled with 50 μL of LPS (4 mg/kg) on day 0 and were mechanically ventilated 1, 4 or 10 days after ARDS induction. (A-D) Lung function parameters resistance (Rrs), elastance (Ers), tissue damping (G) and tissue elastance (H) on day 1, 4 and 10 after ARDS-induction following acetylcholine stimulation) (n = 8 in each group at each time point, means ± SEM). * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (PDF 304 kb)

Introduction: Systemic autoimmune diseases, like SLE are often characterized by a failure of self-tolerance and result in uncontrolled activation of B cells and effector T cells. IL-2 critically maintains homeostasis of regulatory T (Treg) cells and effector T cells in the periphery. Previously, we [for full text, please go to the a.m. URL], 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Systemic lupus erythematosus (SLE) is a fatal autoimmune disease which affects nearly all organs in the human body. Despite the severity of disease treatment options are scarce apart from immune suppression. T cells are critical players in SLE. One factor which contributes to T cell pathophysiology in SLE is an enhanced expression of the cAMP response element modulator (CREM)alpha, a transcription factor, which contributes to several abnormalities in these cells. In my thesis I analyzed the role of CREMalpha in T cells in vitro and in vivo. To explore the relevance of CREMalph in vivo in a lupus setting we crossed CD95 (fas) knock-out mice into mice which overexpress CREM in T cells (fas-/- CREM TG). The CREM TG fas-/- CREM TG mice mice suffered from severely accelerated lymphadenopathy and splenomegaly much earlier in life than wildtype fas-/- animals. Lymphadenopathy and splenomegaly was caused by a massively enhanced expansion of double negative T cells (CD3+CD4-CD8-, DNTs), a reduction of regulatory T cells (Tregs), while amounts IL-17 and IL-21 secreting cells were increased compared to fas-/- mice without CREMalpha overexpression. To our knowledge this is the first report that overexpression of CREMalpha aggravates autoimmunity in vivo. We further analyzed the role of CREMalpha in regulatory T cells and Th17 cells in a CREM knock-out mouse model (CREM-/-) and in a mouse, which selectively overexpresses CREMalpha in T cells (CREM TG). When we generated inducible Tregs from naïve CD4+ T cells the overall expression of Foxp3+ T cells was higher in wildtype T cells than in CREM TG T cells. Vice versa the expression of inducible Tregs generated from CREM-/- mice was significantly higher than from wildtype mice. Furthermore, the knock-out of CREM enhanced the suppressive capacity of Tregs in mice in vitro in suppressionassays and in vivo in a mouse model of transfercolitis. Coimmunprecipitation experiments indicated that CREMalpha interacts with FOXP3 in Tregs. Furthermore microarray analyses identified several genes which might be regulated by CREMalpha in Tregs. We furthermore analysed the role of CREMalpha in Th17 cells in vitro and noticed enhanced development of Th17 cells in CREM TG mice while the fraction of IL-17 producing T cells was reduced in CREM-/- mice compared to wildtype mice. The functional relevance of the enhanced Th17 response in CREM TG mice was demonstrated by two in vivo colitis models. We detected an important mechanism of CREM driven IL-17 expression by mean of chip assays which revealed a CREM binding to the IL17a promotor. Summing up these data indicate a role of CREMalpha for the functionality of Tregs and Th17 cells in vitro and in vivo. We next asked if CREMalpha also influences follicular helper T cells (Tfhs) and B cell responses. CREMalpha enhanced the expression of Tfhs, germinal center(GC) B cells and led to increased serum levels of autoantibodies in fas-/- mice. Moreover CREM TG mice showed enhanced levels of follicular helper T cells, GC B cells and higher specific IgG levels in sera after immunization compared to wildtype mice. These experiments expand the role of CREMalpha as a transcription factor expressed in T cells, which significantly alters B cell response. This thesis confirms a pathogenic role of CREMalpha in vivo and provides evidence that the expression of CREMalpha in T cells of patients with SLE does not represent an epiphenomenon. Moreover CREMalpha might be a new transcription factor which is crucial for the regulation of Tregs, Th17 and Tfh cells. This work therefore contributes to the understanding of the complex transcription factor network in T cell subsets.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin affecting virtually all organ systems. Beyond genetic and environmental factors, cytokine imbalances contribute to immune dysfunction, trigger inflammation, and induce organ damage. The key cytokine that is involved in SLE pathogenesis is interferon alpha. Interferon secretion is induced by immune complexes and leads to upregulation of several inflammatory proteins, which account for the so-called IFN signature that can be found in the majority of SLE PBMCs. Additionally IL-6 and IFN-y as well as T-cell-derived cytokines like IL-17, IL-21, and IL-2 are dysregulated in SLE. The latter induce a T-cell phenotype that is characterized by enhanced B-cell help and enhanced secretion of proinflammatory cytokines but reduced induction of suppressive T cells and activation-induced cell death. This paper will focus on these cytokines and highlights pathophysiological approaches and therapeutic potential.