IntroductionSince their discovery 15 years ago, 1 it is now well established that CD25 ϩ regulatory T cells (Tregs) are indispensable for immune homeostasis and self-tolerance. Tregs suppress the activation, proliferation, and effector functions of a wide range of immune cells via multiple mechanisms. 2 FOXP3 has been identified as a master transcription factor, controlling both Treg development and functionality. 3,4 In addition, human Tregs can be identified by high CD25 and low IL-7 receptor (CD127) expression. 5,6 A critical role of Tregs in controlling autoimmune responses is demonstrated in various animal models of autoimmune disease. 7 Furthermore, lack of functional Tregs leads to severe, systemic autoimmunity in humans. 8,9 Because of their unique function, Tregs are considered important for the treatment of autoimmune disease, and several strategies are now being explored to target these cells for therapeutic purposes. 10 However, there is still an ongoing debate whether the numbers and/or function of Tregs are changed in patients suffering from chronic autoimmune inflammation. 11 In rheumatoid arthritis (RA) and multiple sclerosis, similar Treg numbers,12,13 or even enhanced numbers in RA, 14 were observed in peripheral blood (PB) of patients compared with healthy controls (HCs). Thus, it appears that Treg numbers are not reduced in patients suffering from autoimmune inflammation. In addition, it remains unclear whether Treg function is impaired; some studies report reduced functioning of Tregs in PB of patients, 12,13,15 whereas others have found no difference. 14,16 In addition to these discrepancies concerning Treg numbers and function in the periphery, characterization of Tregs functionality at the site of autoimmune inflammation in humans is missing. High levels of Tregs have been found at the inflammatory sites in patients with arthritis and inflammatory bowel disease and these cells can suppress CD4 ϩ CD25 Ϫ effector cells in vitro. 17 Also at the site of inflammation in juvenile idiopathic arthritis (JIA), one of the most common childhood autoimmune diseases, we have previously shown that Tregs are present in high numbers and suppress proliferation of CD4 ϩ CD25 Ϫ effector cells in vitro. 18 However, in vivo inflammation persists despite the large numbers of Tregs present, suggesting that these cells are defective in their ability to control the ongoing autoimmune response. This may result from the local proinflammatory environment, because in vitro experiments have shown that pro-inflammatory cytokines can affect both Treg function 15,[19][20][21] as well as effector T-cell responses. 22,23 These data suggest that increasing Treg numbers or enhancing function for therapeutic purposes might be less effective in a chronic inflammatory environment. However, ex vivo data from patients with autoimmune disease are required to clarify the role of Tregs at the site of inflammation in humans.Here, we studied Treg function at the site of inflammation in patients with JIA and compared their inhibitory p...

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.

Neutrophil activation and recruitment to the site of infection are critical for host immunity. In humans, the cysteine protease Staphopain A of the pathogen S. aureus blocks this process by cleaving the chemokine receptor CXCR2.

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.

Key Points Autologous HSCT induces functional renewal of regulatory T cells as well as a strong Treg TCR diversification in autoimmune patients. Adding regulatory T cells to the graft does not lead to additional clinical improvement but results in delayed donor T-cell reconstitution.

Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.

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Conclusion. This study is the first to show that anti-TNF␣ targets the resistance of Teff cells to suppression, resulting in improved regulation of inflammatory effector cells.