Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4

The contribution of self-peptide-MHC signaling in CD

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function by Juliet Marie Bartleson Doctor of Philosophy in Biology and Biomedical Sciences Immunology Washington University in St. Louis, 2021 Professor Paul M. Allen, Chair Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions do not propagate canonical TCR activation pathways, but they do engage proximal TCR signaling molecules and affect basal gene expression patterns. Here, we question whether the strength of tonic signaling directly tunes CD4+ T cell function. Utilizing a transgenic TCR system, we uncover a role for tonic signaling in predisposing a CD4+ T cell to either T effector (Teff) or T follicular helper (Tfh) lineage commitment early after activation. We then extend these findings to the polyclonal CD4+ T cell repertoire, and through a series of genetic mouse models, we confirm that direct manipulation of tonic signaling strength alters Tfh development. Ultimately, these data establish an inverse relationship between the strength of tonic TCR signaling and Tfh differentiation. Furthermore, we determine tonic signaling strength is also controlling the overall basal metabolic activity of CD4+ T cells, which corresponds with the production of mitochondrial reactive oxygen species. This offers a potential mechanism for how tonic signaling strength influences TCR activation to skew CD4+ T cell fate decisions. During the course of these studies we generated a novel mouse strain, H2-DMaf/f, to reduce the presentation of self-pMHC, thereby decreasing tonic signaling strength in polyclonal CD4+ T cells. Employing this mouse line, we also interrogated whether there is a specific subset of antigen presenting cells (APCs) responsible for maintaining CD4+ T cell tonic signaling. Our findings indicate a CD11c+ subset of APCs independent of the conventional DC1 lineage is responsible for CD4+ T cell tonic signaling maintenance. Collectively, this work elucidates the critical involvement of tonic signaling in early Teff versus Tfh lineage commitment and enhances our basic understanding of how tonic signaling is being maintained to regulate cellular metabolism during homeostasis

Tuning immunity through tissue mechanotransduction.

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of 'danger signal' that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response

A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation

International audienc

Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight

Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space