Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.

Meal skipping has become an increasing trend of the modern lifestyle that may lead to obesity and type 2 diabetes. We investigated whether the timing of meal skipping impacts these risks by affecting circadian regulation of energy balance, glucose metabolism, and postprandial inflammatory responses. In a randomized controlled crossover trial, 17 participants [body mass index (in kg/m): 23.7 ± 4.6] underwent 3 isocaloric 24-h interventions (55%, 30%, and 15% carbohydrate, fat, and protein, respectively): a breakfast skipping day (BSD) and a dinner skipping day (DSD) separated by a conventional 3-meal-structure day (control). Energy and macronutrient balance was measured in a respiration chamber. Postprandial glucose, insulin, and inflammatory responses in leukocytes as well as 24-h glycemia and insulin secretion were analyzed. When compared with the 3-meal control, 24-h energy expenditure was higher on both skipping days (BSD: +41 kcal/d; DSD: +91 kcal/d; both < 0.01), whereas fat oxidation increased on the BSD only (+16 g/d; < 0.001). Spontaneous physical activity, 24-h glycemia, and 24-h insulin secretion did not differ between intervention days. The postprandial homeostasis model assessment index (+54%) and glucose concentrations after lunch (+46%) were, however, higher on the BSD than on the DSD (both < 0.05). Concomitantly, a longer fasting period with breakfast skipping also increased the inflammatory potential of peripheral blood cells after lunch. Compared with 3 meals/d, meal skipping increased energy expenditure. In contrast, higher postprandial insulin concentrations and increased fat oxidation with breakfast skipping suggest the development of metabolic inflexibility in response to prolonged fasting that may in the long term lead to low-grade inflammation and impaired glucose homeostasis. This trial was registered at clinicaltrials.gov as NCT02635139.

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Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.