TCRαβ thymocytes differentiate to either CD8αβ cytotoxic T lymphocytes or CD4+ T helper cells. This functional dichotomy is controlled by key transcription factors, including the T helper master regulator, ThPOK, which suppresses the cytolytic program in MHC class II-restricted CD4+ thymocytes. ThPOK continues to repress CD8-lineage genes in mature CD4+ T cells, even as they differentiate to T helper effector subsets. Here we show that the T helper-fate was not fixed and that mature antigen-stimulated CD4+ T cells could terminate Thpok expression and reactivate CD8-lineage genes. This unexpected plasticity resulted in the post-thymic termination of the T helper-program and the functional differentiation of distinct MHC class II-restricted CD4+ cytotoxic T lymphocytes.

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

Dendritic cells (DC) represent a heterogeneous population of antigen-presenting cells that are crucial in initiating and shaping immune responses. Although all DC are capable of antigen-uptake, processing, and presentation to T cells, DC subtypes differ in their origin, location, migration patterns, and specialized immunological roles. While in recent years, there have been rapid advances in understanding DC subset ontogeny, development, and function in mice, relatively little is known about the heterogeneity and functional specialization of human DC subsets, especially in tissues. In steady-state, DC progenitors deriving from the bone marrow give rise to lymphoid organ-resident DC and to migratory tissue DC that act as tissue sentinels. During inflammation additional DC and monocytes are recruited to the tissues where they are further activated and promote T helper cell subset polarization depending on the environment. In the current review, we will give an overview of the latest developments in human DC research both in steady-state and under inflammatory conditions. In this context, we review recent findings on DC subsets, DC-mediated cross-presentation, monocyte-DC relationships, inflammatory DC development, and DC-instructed T-cell polarization. Finally, we discuss the potential role of human DC in chronic inflammatory diseases.

Introduction: Dupilumab has recently been approved for the treatment of moderate to severe atopic dermatitis (AD) in adults. Daily practice data on dupilumab treatment are scarce. Objective: To study the effect of 16-week treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate-severe AD in daily practice. Methods: Data were extracted from the BioDay registry, a prospective multicenter registry. Sixteen-week clinical effectiveness of dupilumab was expressed as number of patients achieving EASI-50 (Eczema Area and Severity Index) or EASI-75, as well as patient-reported outcomes measures (Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus). Twenty-one biomarkers were measured in patients treated with dupilumab without concomitant use of oral immunosuppressive drugs at five different time points (baseline, 4, 8, 12, and 16 weeks). Results: In total, 138 patients treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult-to-treat AD, including 84 (61%) patients who failed treatment on ≥2 immunosuppressive drugs. At week 16, the mean percent change in EASI score was 73%. The EASI-50 and EASI-75 were achieved by 114 (86%) and 82 (62%) patients after 16 weeks of treatment. The most reported side effect was conjunctivitis, occurring in 47 (34%) patients. During dupilumab | 117 ARIËNS et Al.

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...