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Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.

Background: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine., Methods: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [ 13 C] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice., Findings: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [ 13 C]-tracing revealed that co-stimulated CD4 + T cells exposed to L-/D-kynurenine undergo increased β-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 μM, which is close to human kidney (6 μM) and head and neck cancer (14 μM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1 -/- mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection., Interpretation: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials., Funding: The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non-COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.

Diabetes mellitus type II (DM) and immune cell infiltration determine patient outcome in many tumor entities. Here we studied a possible link between the metabolic and immune cell status of OSCC patients. Glucose transporter (GLUT) 1 mRNA expression was elevated in all tumor samples, whereas other glycolytic markers such as lactate dehydrogenase (LDH) A or monocarboxylate transporter (MCT) 1 were increased in tumor samples from patients with diabetes and these patients had a significantly worse prognosis compared to non-diabetic patients. Analyses of immune cell infiltration in tumors from diabetic and non-diabetic patients revealed an increased leukocyte (CD45 + ) infiltration compared to normal mucosa only in non-diabetic patients. In line, the amount of CD3 + T cells per mm 2 tumor tissue, was elevated in patients without diabetes and crucial for patient outcome in OSCC patients without diabetes, as compared to healthy mucosa using fluorescence immunohistochemistry in tissue microarrays of 229 patients. Our results demonstrate that diabetes is a prognostic factor for OSCC patients and associates with decreased leukocyte and CD3 + infiltration indicating that metabolic differences between diabetic and non-diabetic patients may alter tumor-infiltrating T cells and thereby determine patient outcome., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Indole is produced from l-tryptophan by commensal bacteria and further metabolized to indoxyl 3-sulfate (I3S) in the liver. Physiologic concentrations of I3S are related to a lower risk to develop graft versus host disease in allogeneic stem cell transplanted patients pointing towards an immunoregulatory function of I3S. Here we investigated the impact of I3S on the maturation of human monocyte-derived dendritic cells (DCs). Even pathophysiologic concentrations of I3S did not affect viability of mature DCs, but I3S decreased the expression of co-stimulatory molecules such as CD80 and CD86 on mature DCs. Furthermore, I3S inhibited IL-12 and IL-6 secretion by mature DCs while IL-10 was significantly upregulated. Co-culture of I3S-treated mature DCs with allogeneic T cells revealed no alteration in T cell proliferation. However, interferon gamma and TNF production of T cells was suppressed. As I3S exerted no direct effect on T cells, the defect in T cell activation was mediated by I3S-treated mature DCs. Our study suggests an anti-inflammatory and tolerizing effect of I3S on human DCs., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha low ) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2 -/- γc -/- mice, lacking lymphocytes and NK cells, and in Ifng -/- mice, Ldha low and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vaccination is among the most efficient forms of immunotherapy. Although sometimes inducing lifelong protective B-cell responses, T-cell-mediated immunity remains challenging. Targeting antigen to dendritic cells (DCs) is an extensively explored concept aimed at improving cellular immunity. The identification of various DC subsets with distinct functional characteristics now allows for the fine-tuning of targeting strategies. Although some of these DC subsets are regarded as superior for (cross-) priming of naive T cells, controversies still remain about which subset represents the best target for immunotherapy. Because targeting the antigen alone may not be sufficient to obtain effective T-cell responses, delivery systems have been developed to target multiple vaccine components to DCs. In this Perspective, we discuss the pros and cons of targeting DCs: if targeting is beneficial at all and which vaccine vehicles and immunization routes represent promising strategies to reach and activate DCs.

A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid-free medium restored CTL function. CTLs infiltrating lactic acid-producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.