Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11β-hydroxysteroid dehydrogenase type 1; 11β -HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1β, or TNF-α. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes.

Highlights d Pregnancy modulates the T cell repertoire in MS in a clonally specific fashion d ''Private'' candidate clones associated with disease activity can be identified d Barcoding enables a-b TCR pairing of these clones for further characterization d Most candidate clones do not respond to putative MS autoantigens (e.g., myelin)

Summary Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA ( CPT1a ) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.

Epidemiological, clinical, and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T cell glucocorticoid signaling in patients versus healthy persons as a potential indicator of disease-specific CNS-immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T cell glucocorticoid signaling across groups. This network’s activity was simultaneously linked to patients’ lesion volume, clinical disability and information processing speed. Complementary analyses revealed that T cell glucocorticoid signaling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress-processing and T cell stress hormone sensitivity are related to key severity measures of multiple sclerosis.

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Converging lines of evidence from human studies and experimental models have recently suggested a putative pathogenetic role of mitochondrial biology in neuropsychiatric disorders including depression. However, mitochondrial regulation is tissue-specific and varies substantially between subsets of cell populations, particularly in the immune system, where mitochondrial bioenergetics and dynamics drive cell function. Thus, while the peripheral immune system is an attractive biomarker candidate due to its easy accessibility in humans and its likely involvement in mood disorders, investigations in this area will require detailed workup of cellular specificity and functional implications to gain insight into potentially druggable pathobiological substrates.

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non‐depressed patients with obesity and normal‐weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ‐9). Cell frequencies were correlated with depressive symptom scores and waist‐to‐hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal‐weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non‐depressed patients with obesity and compared to normal‐weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ‐9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ‐9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.

Antibiotic use during pregnancy is associated with increased asthma risk in children. Since approximately 25% of women use antibiotics during pregnancy, it is important to identify the pathways involved in this phenomenon. We investigate how mother‐to‐offspring transfer of antibiotic‐induced gut microbial dysbiosis influences immune system development along the gut–lung axis. Using a mouse model of maternal antibiotic exposure during pregnancy, we immunophenotyped offspring in early life and after asthma induction. In early life, prenatal‐antibiotic exposed offspring exhibited gut microbial dysbiosis, intestinal inflammation (increased fecal lipocalin‐2 and IgA), and dysregulated intestinal ILC3 subtypes. Intestinal barrier dysfunction in the offspring was indicated by a FITC‐dextran intestinal permeability assay and circulating lipopolysaccharide. This was accompanied by increased T‐helper (Th)17 cell percentages in the offspring's blood and lungs in both early life and after allergy induction. Lung tissue additionally showed increased percentages of RORγt T‐regulatory (Treg) cells at both time points. Our investigation of the gut–lung axis identifies early‐life gut dysbiosis, intestinal inflammation, and barrier dysfunction as a possible developmental programming event promoting increased expression of RORγt in blood and lung CD4+ T cells that may contribute to increased asthma risk.