Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy

The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways

Foxp3(+) regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6(-/-) ) mice develop severe and spontaneous T helper type 2 (Th2) inflammation and Bcl6-deficient Treg cells are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyse the fate of Treg cells in these mice. In the periphery of Bcl6(-/-) mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25(+) population. ExTreg cells from Bcl6(-/-) mice expressed increased interleukin-17 (IL-17) and extremely elevated levels of Th2 cytokines compared with wild-type exTreg cells. Although Treg cells normally express only low levels of cytokines, Treg cells from Bcl6(-/-) mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6(Foxp3-/-) ) mice were analysed. Bcl6(Foxp3-/-) mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6(-/-) mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6(Foxp3-/-) mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Treg cells expressed higher levels of the Th2-specific regulator Gata3 than Bcl6(+) Treg cells. Bcl6(Foxp3-/-) mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the bronchoalveolar lavage fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg cell stability and Th2 inflammation, and support the idea that Bcl6 expression in Treg cells is critical for controlling Th2 responses

A földi és az atmoszférikus árapály egyéb geodinamikai hatásai és kapcsolatuk a kőzetek radonkibocsátásával = Geodynamical effect of the Earth's and atmospheric tides and their connection with the radon emanation of rocks

A project keretében párhuzamos strain, légnyomás, hőmérséklet és radonkoncentráció méréseket folytattunk a Sopronbánfalvi Geodinamikai Obszervatóriumban (SGO). Az extenzométer kalibrálási módszerének tökéletesítésével annak pontosságát a korábbi ötszörösére növeltük. Koherencia analízis segítségével teszteltük a FÖLD-obszervatórium-műszer rendszert és kimutattuk, hogy az obszervatórium alkalmas a lokális tektonikai deformációk regisztrálására. Részletesen vizsgáltuk a légnyomás és az extenzométerrel mért strain értékek közötti kapcsolatot. Neurális hálózaton alapuló új módszert fejlesztettünk ki a strain adatok légnyomással történő korrekciójára. Numerikus kapcsolatot találtunk a hosszúidejű strain és radonkoncentráció változások között. A radonkoncentráció adatokat spektrum- és árapályelemzésnek vetettük alá. Árapály komponenseket azonban nem tudtunk egyértelműen kimutatni a radonkoncentráció adatokban. Az extenzométeres mérések változó sebességű kompressziós strain-t mutattak az elmúlt húsz évben az SGO-ban. Az extenzométeres mérések eredményeit összehasonlítottuk a Pannon-medencében végzett geodéziai (GPS) és geofizikai strain mérések eredményeivel. Az extenzométerrel mért változó strain sebesség valószínűleg a Keleti-Alpok és a Pannon-medence eltérő emelkedési sebességének, valamint a medencében végbemenő felgyűrődési mechanizmusnak tulajdonítható. Ennek alátámasztására azonban még további vizsgálatokra van szükség. | In the framework of the project simultaneous strain, air pressure, temperature and radon concentration measurements were carried out in the Sopronbánfalva Geodynamic Observatory (SGO). The calibration method of the extensometer was improved and its accuracy was increased by a factor of five. The Earth-observatory-instrument system was tested by coherence analysis and it was pointed out that the observatory is suitable for recording the local tectonic deformations. The relationship between air pressure and strain measured by the quartz-tube extensometer was investigated in detail. A new method based on neural network was developed for correction of strain data by air pressure. Numerical connection was found between the long-term strain and radon concentration variations. Radon concentration data were subjected to spectrum and tidal analysis. Tidal components were not unambiguously detected in the radon concentration data series. The extensometric measurements showed a compressional stress with a changing stress rate in the last 20 years in the SGO. The results of the extensometric measurements were compared with the results of geodetic (GPS) and geophysical strain measurements in the Pannonian Basin. The changing strain rate measured by the extensometer is probably due to the difference of the rising rate of the Eastern Alps and the Pannonian Basin and the folding mechanism in the basin. Further investigations are necessary in the future to confirm this assumption

The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: Another aspect of immune privilege in the CNS

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91232/1/eji2300.pd

Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression

The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway

Predicting athletic performance: the effects of judgment and motivation

The purpose of this study was to examine the influence of athlete motivation and judgment on the relationship between athletic ability and athletic performance. Much existing empirical literature has focused on motivation and cognitive ability in relation to athletic performance, but athlete judgment has received relatively little research attention. It was hypothesized that high performers will have stronger judgment and motivation scores than will lower performers. Results suggest the ability to make strategic decisions as operationalized by Systemic Judgment may be predictive of Athletic Performance

Regulatory T cell stability determines the efficiency of bile duct regeneration during cholangitis

Cholangiopathies such as primary sclerosing cholangitis (PSC) cause damage to the bile ducts with no effective cure. Reduction and impairment in the function of regulatory T cells (Tregs) occur in PSC. We investigate whether Tregs regulate bile duct regeneration and the dynamics of Treg turnover during bile duct injury. We use the transgenic Foxp3GFPDTR model to mimic reduced Treg infiltration in PSC and show that Tregs mediate cholangiocyte response to biliary injury. Fate mapping of Tregs reveals that intrahepatic Tregs acquire a pro-inflammatory phenotype, even after interleukin-2 (IL-2)-mediated Treg expansion. Ox40L expression correlates with fibrosis in PSC patients. Enhancing Treg numbers through IL-2 complex administration and blocking Ox40 signaling simultaneously suppresses the inflammatory phenotype of Tregs and reduces bile duct damage and fibrosis. We demonstrate that bile duct regeneration can be enhanced by combining Treg-based therapy and targeting co-stimulatory molecules, such as Ox40L. </p

Molecular Mechanisms and Antigen Receptor Requirements for Lymphocyte Adaptation to Intestinal Tissues

The intestine plays a crucial role in food digestion, nutrient absorption, water retention, and waste excretion. It contains the most populous immune cell reservoir in the body and is continuously exposed to a large and diverse number of diet- and microbiota- derived antigens. The highly stimulating luminal environment is separated from the core of the body, the lamina propria (LP), by just a single layer of epithelial cells. The intestinal immune system is thus tasked with being able to tolerate innocuous stimuli while mounting an effective response against potential pathogens in a controlled manner. To ensure appropriate balance between tolerance and resistance, T cells undergo tissue adaptation upon migrating from the gut-draining mesenteric lymph nodes (mLN) to the intestinal lamina propria and epithelium (IE). We sought to elucidate the transcriptional mechanisms and T cell receptor (TCR) signaling requirements of CD4+ T cell plasticity and adaptation in the intestinal tissues. Within the intestine, peripherally induced Foxp3+ regulatory T cells (iTregs), which are instrumental in limiting inflammatory responses to non-self antigen, are located primarily in the lamina propria. However, CD8aa-expressing intraepithelial CD4+ T cells (CD4- IELs), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we find distinct cell dynamics of intestinal Tregs and CD4-IELs. We addressed the molecular imprinting of the gut epithelium on T cells by integrating mouse genetics with single-cell RNAsequencing analyses. Transcriptionally, CD4+ T cells from mLN, LP and IE segregate based on the intestinal layer they occupy; trajectory analysis suggests a stepwise loss of CD4-programming and acquisition of an intraepithelial profile as CD4+ T cells adapt to the epithelium and convert to CD4-IELs. We found that upon migration to the epithelium, Tregs can lose Foxp3 expression and convert to CD4-IELs in a microbiota-dependent fashion, an effect in part attributed to loss of the CD4 lineage-defining transcription factor ThPOK. Treg fate-mapping coupled with RNA- and ATAC-sequencing revealed that the Treg program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of Thpok results in premature acquisition of an IEL profile by mLN Tregs, partially recapitulating epithelium imprinting. Furthermore, we demonstrate that iTregs and CD4-IELs perform complementary roles in the regulation of intestinal inflammation in response to dietary antigen. To uncover the specific role of the T cell receptor in the process of CD4-IEL development, we combined in vivo fate-mapping and gene ablation models with single cell TCRsequencing. Single-cell TCR repertoire and transcriptomic analysis of intraepithelial CD4+ T cells revealed different extents of clonal expansion and TCR overlap between cell states; fully differentiated CD4-IELs from regulatory or conventional CD4+ T cells were the least diverse. Conditional deletion of TCR on differentiating CD4+ T cells or of MHCII on intestinal epithelial cells prevented CD4-IEL differentiation. However, TCR ablation on developed CD4-IELs did not affect their accumulation. Overall, our results reveal an inter- and intra-tissue specialization of anti-inflammatory CD4+ T cells shaped by discrete niches of the intestine. We uncovered the stepwise molecular mechanisms and TCR-signaling requirements for T cells to adapt to the intestinal epithelium. We found that the coordinated replacement of the circulating lymphocyte program with site–specific transcriptional and chromatin changes is necessary for tissue imprinting. Furthermore, our results indicate that local recognition of possibly a limited set of antigens is an essential signal for the differentiation and adaptation of T cells to the epithelium. Taken together, the work presented in this thesis demonstrates that a combination of genetic, TCR, and environmental triggers is crucial in driving T cell plasticity and adaptation to the tissues within the intestine