The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microorganisms with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1-4. Although RORγt+ antigen-presenting cells (APCs) have been shown to programme gut microbiota-specific pTreg cells5-7, their definition remains incomplete, and the APC responsible for food tolerance has remained unknown. Here we identify an APC subset that is required for differentiation of both food- and microbiota-specific pTreg cells and for establishment of oral tolerance. Development and function of these APCs require expression of the transcription factors PRDM16 and RORγt, as well as a unique Rorc(t) cis-regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish the pTreg-inducing APCs as myeloid in origin, distinct from type 3 innate lymphoid cells, and sharing epigenetic profiles with classical dendritic cells, and designate them PRDM16+RORγt+ tolerizing dendritic cells (tolDCs). Upon genetic perturbation of tolDCs, we observe a substantial increase in food antigen-specific T helper 2 cells in lieu of pTreg cells, leading to compromised tolerance in mouse models of asthma and food allergy. Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tolDCs with co-expression of PRDM16 and RORC and an extensive transcriptome shared with tolDCs from mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.

A common behavior in natural environments is foraging for rewards. However, this is often in the presence of predators. Therefore, one of the most fundamental decisions for humans, as for other animals, is how to apportion time between reward-motivated pursuit behavior and threat-motivated checking behavior. To understand what affects how people strike this balance, we developed an ecologically inspired task and looked at both within-participant dynamics (moods) and between-participant individual differences (questionnaires about real-life behaviors) in two large internet samples (n = 374 and n = 702) in a cross-sectional design. For the within-participant dynamics, we found that people regulate task-evoked stress homeostatically by changing behavior (increasing foraging and hiding). Individual differences, even in superficially related traits (apathy-anhedonia and anxiety-compulsive checking) reliably mapped onto unique behaviors. Worse task performance, due to maladaptive checking, was linked to gender (women checked excessively) and specific anxiety-related traits: somatic anxiety (reduced self-reported checking due to worry) and compulsivity (self-reported disorganized checking). While anhedonia decreased self-reported task engagement, apathy, strikingly, improved overall task performance by reducing excessive checking. In summary, we provide a multifaceted paradigm for assessment of checking for threat in a naturalistic task that is sensitive to both moods as they change throughout the task and clinical dimensions. Thus, it could serve as an objective measurement tool for future clinical studies interested in threat, vigilance or behavior-emotion interactions in contexts requiring both reward seeking and threat avoidance.

Gender inequality substantially impacts society, disproportionately disadvantaging women, especially in the Global South. This inequality correlates with brain health outcomes for women, including a higher risk of cognitive decline and dementia. This perspective highlights how sex-linked biology and gender disparities affect women's brain health in the Global South through various pathways, such as differential exposome, health behaviors, and gender biases in research and healthcare systems. Alzheimer's disease and other brain health conditions exemplify how sex-specific risk factors and gender-related health barriers interact to influence brain health. We advocate for incorporating sex/gender considerations in research, policy, and clinical practice to improve brain health interventions in the Global South. Additionally, we propose using the patient and public involvement framework to effectively tailor health strategies that address these factors.