Immunity Commons^™

Mitochondria Dynamics In Microglia During Health, Inflammation, And Aging, Alicia Nicole Pietramale

Dartmouth College Ph.D Dissertations

Microglia continually surveil the brain, allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain has remained unclear. In this dissertation, I combine intravital imaging, ultrastructural analyses, and metabolic and cytoskeletal markers to investigate how mitochondrial organization relates to microglial function across health, inflammation, and aging.

I first show that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. This heterogeneous partitioning is conserved …

Macrophage Heterogeneity And Function In The Lung, Xin Li

Dartmouth College Ph.D Dissertations

Macrophages are critical custodians of the lung, orchestrating immune surveillance, maintaining tissue homeostasis, and coordinating both innate and adaptive responses. This dissertation examines their heterogeneity and specialized functions, focusing on IMs, which reside in the lung interstitium, and AMs, which occupy the airspace. Through comprehensive single-cell transcriptomic profiling of murine and human samples, we identify multiple IM and AM subsets defined by distinct chemokine, cytokine, receptor, and innate immune gene signatures. These subsets display clear divisions of labor, contributing to immune cell recruitment, tertiary lymphoid structure formation, and alveolar homeostasis.

In IMs, coordinated chemokine programs not only recruit inflammatory cells …

Mechanisms Of Macrophage Metabolic Activation And Paracrine Wnt Signaling In The Pathogenesis Of Systemic Sclerosis, Emily Ann Morris

Dartmouth College Ph.D Dissertations

Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology. We have previously shown that macrophages (MØs) play a critical role in its pathogenesis; however, the mechanisms driving MØ activation in SSc remain poorly understood. This dissertation investigates the molecular signaling pathways and biochemical mechanisms underlying profibrotic MØ activity in SSc.

First, I identify a novel MØ-specific effect of mycophenolate mofetil (MMF), the standard-of-care treatment for SSc. While MMF is a well characterized lymphostatic, my findings demonstrate that its active metabolite, mycophenolic acid (MPA), is also capable of directly inhibiting myeloid viability and profibrotic MØ activation by suppressing de …

Sounding The Alarm: Local Cues That Drive Functional Specialization Of Brain Resident Memory T Cells, Shawn Christopher Musial Jr.

Dartmouth College Ph.D Dissertations

Resident memory T cells are a unique subset of memory T cells that persist within tissues throughout the body, including the brain, optimally positioned to exert local immune activation. Broadly, T cells in the CNS are implicated in a range of neurologic disorders, can protect against reinfection, and even participate in normal CNS homeostasis. Despite this, there remain significant gaps in knowledge about how T cells, specifically resident memory T cells (T_RM), are regulated and function in the unique CNS environment. Here, we leverage a mouse model of acute viral infection to dissect the diversity of brain T …

Establishment Of Bacteroides In The Gut And Its Role In The Cystic Fibrosis Gut-Lung Axis, Rebecca A. Valls

Dartmouth College Ph.D Dissertations

In the quest to understand the complex interplay between the gut microbiota and cystic fibrosis (CF), a disease characterized by chronic upper respiratory complications and an exacerbated proinflammatory response, our lab engaged in a collaborative study with Dartmouth-Hitchcock Medical Center (DHMC) to characterize the gut microbiota of pediatric CF patients. Initial analyses established a connection between gut microbial composition and respiratory health, particularly highlighting a scarcity of Bacteroides species compared to healthy controls. In following investigations, we utilized random forest models to understand how stool microbiota may influence clinical outcomes of these pediatric CF patients, including: age, upper respiratory infections, …

Hierarchal Single-Cell Lineage Tracing Reveals Differential Fate Commitment Of Cd8 T-Cell Clones In Response To Acute Infection., Leena Abdullah

Dartmouth College Ph.D Dissertations

Generating balanced populations of CD8 effector and memory T cells is necessary for immediate and durable immunity to infections and cancer. Yet, a definitive understanding of CD8 differentiation remains unclear. Here we used CARLIN, a processive lineage recording mouse model with single-cell RNA-seq and TCR-seq to track endogenous antigen-specific CD8 T cells during acute viral infection.

Transcriptional profiling of antigen-specific T cells at the peak of the effector response to Vesicular stomatitis virus uncovered a diverse repertoire of expanded antigen-specific T-cell clones represented by seven transcriptional states. TCR enrichment analysis identified TCR clones with differential memory- or effector-fate biases during …

Regulation And Therapeutic Targeting Of Virus-Specific Resident Memory T Cells, Jordan Fredriksen Isaacs

Dartmouth College Ph.D Dissertations

CD8+ T cells are critical to the immune response to pathogens, as they kill infected cells and generate immunologic memory. Following infection, antigen-specific T cells expand approximately 10,000-fold and migrate to sites of inflammation in order to clear the pathogen. Once infection is resolved, a small pool of memory T cells persist in circulation and within tissues ready to respond rapidly upon re-exposure. Given the importance of CD8+ T cells, significant efforts have been made over the years to better understand how different memory T cell subsets are established, maintained, and regulated. The most recently identified subset, resident memory T …

Heterogeneity And Plasticity Of The Naïve Cd4+ T Cell Compartment, Alia Sajani

Dartmouth College Ph.D Dissertations

Recent studies have illuminated unexpected heterogeneity in the naïve T cell compartment. Using single cell RNA sequencing of mouse naïve CD4⁺ T cells, we identified 5 unique transcriptional subsets within the naïve CD4⁺ T cell compartment. These include a quiescence cluster (T^Q) marked by Klf2, Klf6, Jun and Btg2, a memory-like cluster (T^MEM) marked by Ccr7, Il7r and Tcf7, a TCR reactive cluster (T^TCR) marked by Cd5, Cd6 and Nr4a1, an IFN responsive cluster (T^IFN) marked by Stat1, Irf7 and Ifit1 and …

Molecular Mechanisms Governing The Generation Of Tissue Resident Memory Cd8 T Cells In The Setting Of Cancer, Nikhil Khatwani

Dartmouth College Ph.D Dissertations

Although there has been extensive research on T-cell responses to cancer immunotherapy, the understanding of long-lasting memory in visceral organs remains less well understood. Among these, a population of Trm cells was discovered that reside durably within tumor draining lymph nodes (TDLN) and plays a crucial role in protecting against invading melanoma cells, uncovering a new role for Trm cells at critical metastatic sites. However, little is known about the molecular mechanisms promoting Trm establishment in tissues where cancer can develop and metastasize. Here, employing longitudinal T cell receptor (TCR)-lineage-tracing and single-cell transcriptomics, we find that TDLN contain Teff cells …

Response And Molecular Control Of Cd8 T Cells During Infection And Cancer, Nicholas K. Preiss Dr.

Dartmouth College Ph.D Dissertations

CD8 T cells are potent immune effector cells capable of vast clonal expansion and clearance of infected or cancerous cells. After control of the pathogenic insult, CD8 T cells develop into quiescent, long-lived memory populations that are poised to mediate rapid protection upon reencounter with cognate antigen. These properties make control of CD8 T cell responses a highly desirable outcome of vaccine strategies and immunotherapy. Therefore, understanding how the effector function and memory differentiation of CD8 T cells are controlled at a molecular level is of great importance. In the context of infection with gammaherpesviruses (γHV), which form a latent …