Unraveling Molecular Mechanisms Underlying the Development of Unconventional T Cells

The thymus supports and guides the generation of a diverse repertoire of mature T cells from precursors derived from the bone marrow. In addition to conventional CD4 and CD8 T cells, innate-like T cells also develop in the thymus and share features of the adaptive and the innate immune system. These ‘unconventional’ T cells have emerging roles in tissue homeostasis and disease, but the molecular mechanisms underpinning their development remain elusive. In this study, we uncovered the roles of the molecules RAPTOR and PTEN in the thymic development of unconventional T cells. Capitalizing on genetic deletion of RAPTOR, we found RAPTOR-dependent mTORC1 signaling couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages: αβ and γδ-T cells. Loss of RAPTOR impaired αβ but promoted γδ-T cell development while disrupting metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identified mTORC1-dependent control of reactive oxygen species (ROS) production as a key metabolic signal that, upon perturbation of redox homeostasis, impinges upon T cell fate decisions. Additionally, we showed that PTEN acts as a cell-intrinsic molecular brake for the thymic development of unconventional T cells. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices and uncover PTEN as a cell-intrinsic molecular brake in the development of unconventional T cells

Metabolic signaling directs the reciprocal lineage decisions of αβ and γδ T cells

Wiring metabolic signaling circuits in thymocytes Cell differentiation is often accompanied by metabolic changes. Yang et al. report that generation of double-positive (DP) thymocytes from double-negative (DN) cells coincides with dynamic regulation of glycolytic and oxidative metabolism. Given the central role of mechanistic target of rapamycin complex 1 (mTORC1) signaling in regulating metabolic changes, they examined the role of mTORC1 pathway in thymocyte development by conditionally deleting RAPTOR, the key component of the mTORC1 complex, in thymocytes. Loss of RAPTOR impaired the DN-to-DP transition, but unexpectedly also perturbed the balance between αβ and γδ T cells and promoted the generation of γδ T cells. Their studies highlight an unappreciated role for mTORC1-dependent metabolic changes in controlling thymocyte fates. The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the αβ and γδ T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of αβ T cells but promotes γδ T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating αβ and γδ T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal αβ and γδ T cell development and provide insight into metabolic control of cell signaling and fate decisions. Development of αβ and γδ T cells requires coupling of environmental signals with metabolic and redox regulation by mTORC1. Development of αβ and γδ T cells requires coupling of environmental signals with metabolic and redox regulation by mTORC1

Health literacy on quality of life for children with cancer: modules on pediatric palliative care

Objective. To describe the development of educational materials for parents and other caregivers of children with cancer, which utilized a culturally sensitive approach to reduce acceptance barriers to palliative care (PC). Methods. The Pan American Health Organization (PAHO), St. Jude Children’s Research Hospital, and partners in Latin America and the Caribbean collaborated in a three-phase project, beginning with a needs assessment survey of caregivers of children with cancer in Peru. Based on this finding, an interdisciplinary team of pediatric PC experts developed educational content that was designed and validated by an international committee of PC and communication experts. Results. The collaboration resulted in the development of an eight-module series that introduces caregivers to key concepts of pediatric PC, including management of pain, quality of life, and end of life care. The series was designed to reduce caregiver stigma associated with PC through culturally sensitive education that addresses the low levels of health literacy among caregivers in Latin America and the Caribbean. In the 15 months since the launch, these modules have been distributed throughout Latin America and were downloaded 2 825 times. Conclusions. Educational materials and anticipatory guidance of PC were considered to be a priority for parents and other caregivers of children with cancer throughout Latin America. The materials developed through this project have been widely utilized and are available through the PAHO website and the Together by St. Jude online resource

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signaling

Regulatory T cells (Treg cells) play a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis1,2. Transcriptional programming of regulatory mechanisms facilitates Treg cell functional activation in the prevention of diverse types of inflammatory responses3,4. How Treg cells orchestrate their homeostasis and interplay with environmental signals remains poorly understood. Here we show that liver kinase B1 (LKB1) programs proper metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1, and TNF receptor (TNRF) superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signaling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signaling for the proper control of PD-1 and TNFR proteins. Blockade of PD-1 activity reinvigorated the suppressive capability of LKB1-deficient Treg cells in the repression of TH2 responses and the interplay with thymic stromal lymphopoietin (TSLP)-primed dendritic cells (DCs). Thus, Treg cells employ LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance