Research Projects

Lab Mission: Characterizing the Cellular Anatomy and Physiology of Human T Cells to Understand HIV Pathogenesis and to Elicit Elite Control in Normal Progressors

Human T Cell Biology:

Our laboratory investigates the complex interplay between the three-dimensional cellular architecture and metabolic changes that occur within T cells over time, which in turn influence cell migration and effector functions. By studying the metabolic and mechanical signals involved in progressive HIV infection or HIV control, we strive to unravel the cytoskeletal re-arrangements, lipid vesicle trafficking, and chromatin accessibility that shape T cell behavior.

Cytoskeletal & Membrane Organization:

The anatomy of T cells is governed by dynamic cytoskeletal organization, which is distinct from many other somatic cells but shares similarities with other leukocytes. While circulating in the blood, T cells possess retracted actin and microtubule networks. However, upon extravasation into lymphoid or peripheral tissues, T cell morphology becomes polarized. The leading edge of the cell is characterized by multiple actin-myosin networks that propel the cell forward. Situated posteriorly to the leading edge and nucleus are the centrosome and microtubular network, accompanied by the intermediate filament Vimentin. These cytoskeletal structures adapt to the changing microenvironment during T cell migration and establish connections between intracellular components and the plasma membrane.

Mechanics of T Cell Migration:

Understanding the mechanics of T cell migration is crucial for deciphering the processes that govern immune surveillance and tissue infiltration. We investigate the factors and molecular pathways involved in T cell migration, enabling us to comprehend the key determinants of T cell trafficking within the body.

Metabolism and Cell Function:

Metabolic reprogramming is a fundamental aspect of T cell biology. Our research focuses on uncovering the link between cellular metabolism and T cell function. By elucidating the metabolic requirements of T cells during HIV infection or control, we aim to uncover novel targets for therapeutic intervention.

Intracellular and Intercellular Signaling:

Effective T cell responses rely on intricate signaling networks. Our laboratory investigates the interplay between intracellular and intercellular signaling pathways that regulate T cell activation, differentiation, and effector functions. We aim to unravel the signaling cascades underlying T cell fate decisions and immune responses against HIV.

Phosphoinositides & Vesicle Trafficking:

Phosphoinositides and vesicle trafficking play crucial roles in T cell biology. We focus on dissecting the mechanisms by which phosphoinositides and vesicle trafficking events modulate T cell activation, migration, and communication with other cells within the immune system.

Dynamic Nuclear Architecture:

The nuclear architecture of T cells is highly dynamic and tightly regulated. We investigate the changes in chromatin accessibility, gene expression, and nuclear organization that occur during T cell activation, differentiation, and response to HIV infection. By understanding the dynamic nuclear architecture of T cells, we aim to unravel the mechanisms underlying T cell fate determination.

T Cells Within Tissues

Spatial Transcriptomics & Proteomics:

In our laboratory, we employ spatial-omics techniques to gain insight into the gene and protein expression profiles within specific regions of tissues. By integrating spatial information with transcriptomic and proteomic data, we aim to elucidate the spatial organization of T cells and their interactions with other cell types in various contexts, including HIV infection.

Human Lymph Nodes:

Lymph nodes are important immune organs where T cell activation and immune responses take place. We investigate the cellular architecture and molecular dynamics within human lymph nodes to understand the mechanisms underlying T cell trafficking, antigen presentation, and immune regulation. By studying lymph nodes, we aim to uncover novel strategies for modulating T cell responses during HIV infection.

CNS Tissues:

The central nervous system (CNS) is a unique environment in the context of HIV infection, as it serves as a reservoir for viral persistence. We utilize non-human primate models, specifically Rhesus macaques, to study the cellular anatomy and immune response within CNS tissues during HIV infection. By characterizing the T cell and microglial dynamics along with other immune interactions within the CNS, we aim to unravel the mechanisms underlying HIV-associated neuroinflammation and identify potential therapeutic targets.

3D Human Tissue Models:

To mimic the complexity of human tissues in a controlled environment, we employ 3D tissue models. These models provide a valuable platform for studying T cell behavior and interactions within a tissue-like context. By using 3D tissue models, we aim to bridge the gap between traditional cell culture and in vivo studies, enabling us to investigate T cell biology in a more physiologically relevant setting.

Ex Vivo Tonsil Histoculture:

Tonsils are secondary lymphoid organs that serve as important sites for T cell differentiation and immune responses. We utilize ex vivo human tonsil histoculture models to investigate the dynamics of T cell migration, activation, and effector functions within the tonsil microenvironment. By studying tonsil histocultures, we aim to gain insights into the mechanisms underlying HIV infection and elite control within the tonsil tissue.

Human Thymic Histoculture:

The thymus is the primary site of T cell development and maturation. To understand the processes involved in T cell selection and differentiation, we utilize human thymic histoculture models. These models allow us to investigate the interactions between thymic epithelial cells, antigen-presenting cells, and developing T cells, providing valuable insights into the cellular mechanisms underlying T cell development and HIV pathogenesis.

CNS Organoid Model:

To study the interactions between T cells and CNS tissues in a more controlled and reproducible manner, we employ iPSC-derived CNS organoid models. These 3D organoids recapitulate key features of the CNS microenvironment, allowing us to investigate the behavior and responses of T cells within a complex neural context. By using CNS organoid models, we aim to uncover the mechanisms involved in T cell migration, viral persistence, and immune responses within the CNS during HIV infection.

Colon & Liver Organoid Models:

In addition to studying T cell biology in lymphoid and CNS tissues, we also investigate T cell behavior within the context in peripheral tissues affected by HIV infection. We utilize colon and liver organoid models to explore the interactions between effector and resident memory T cells and these tissues, shedding light on the mechanisms underlying T cell dysfunction and tissue-specific pathologies in HIV-infected individuals. These organoid models provide a valuable tool for understanding the complex interplay between T cells and non-lymphoid organs during HIV infection.

Through our comprehensive research approach, combining studies on cellular anatomy, physiology, pathology, and 3D tissue models, we strive to unravel the intricate mechanisms underlying HIV-induced T cell dysfunction and identify novel therapeutic strategies for combating HIV/AIDS.

Furler O'Brien Laboratory

Furler O'Brien Laboratory

Research Projects

T Cells Within Tissues

Video

T Cell Activation