Our laboratory’s two main lines of investigation aim to understand T cell mediated inflammation in chronic disease combining vascular immunology and cardiac physiology approaches in vitro and in vivo:
- Study the mechanisms that regulate Th17 cell recruitment to sites of inflammation;
- Study the role of T cell immune responses in heart failure, including the mechanisms triggering T cell recruitment into the heart and their impact in cardiac myocyte and cardiac fibroblast function.
T Cell Recruitment During Inflammation
Inflammation is a key pathophysiological process in a large number of common diseases where different subsets of T cells can contribute in distinct ways. The selective recruitment of a particular T cell subset into tissues during inflammation is tightly regulated, depends on the type of inflammatory response and involves interactions between specific ligands expressed on the T cell surface (selectin ligands and integrins) with their respective adhesion molecules expressed on the vascular endothelium (selectins and intercellular and vascular adhesion molecules ICAM-1/ICAM-2 and VCAM-1) in combination with appropriate chemokines. Our lab focuses on how Th17cells migrate to inflamed tissues. We employ an in vitro flow model for direct microscopic examination of Th17 cell interactions with activated endothelial cells under defined shear stress conditions. Live cells are imaged using combined Differential interference contrast (DIC) and fluorescence microscopy. The in vitro observations are corroborated in vivo using different models of acute and chronic inflammation and two models of autoimmunity in mice deficient in adhesion molecules identified to be important for Th17 cell recruitment.
Figure 1. Sequence of steps in the leukocyte recruitment cascade. Circulating leukocytes in the bloodstream initially attach to activated endothelium by selectin-mediated and α4β1 integrin-mediated interactions involved in the initial rolling step. The leukocytes locomote on the endothelial cell vessel wall by establishing Mac-1 integrin-mediated interactions with ICAM-1 on the endothelial cells until they firmly arrest near cell-cell junctions. This step is followed by stronger interactions mediated by several endothelial cell molecules besides ICAM-1, in which the leukocyte squeezes through the endothelial cell junction.
You do not have Adobe Flash installed. Please install it to view this movie.
Figure 2. Differential interference contrast (DIC) microscopy imaging of Th17 cells (green) and Th1 cells (red) interactions with mouse heart endothelial cells stimulated 4-hr with TNF alpaha under conditions of shear stress (1 dyne/cm2).)
T Cell Immune Responses in Non-Ischemic Heart Failure
Heart Failure (HF) is a leading cause of morbidity and mortality. This progressive syndrome is generally caused by a decline in left ventricular (LV) function that increases LV pressure and activates LV hypertrophy and fibrosis, a process known as cardiac remodeling. Chronic inflammation has been recently associated with the pathophysiology of HF, however the inflammatory mechanisms involved are largely unexplored to date. Our lab uses the mouse model of pressure overload induced HF to study the role of T cells and T cell subsets in HF, the mechanisms triggering T cell recruitment to the heart, and the ways infiltrated T cells impair cardiac function. As a translational approach, our lab also uses a combination of experimental approaches using T cells and Left ventricular tissues from patients with HF to study the role of T cells in human non-ischemic HF.
Figure 3. A. Mouse model of non-ischemic pressure overload induced heart failure. TAC induces cardiac stress by increasing LV pressure overload (~60mmHg) that results in cardiac remodeling (B) and mimics the pathophysiology of HF. C. Example of CD4+ T cells from mice 4 weeks after TAC going through the steps of the leukocyte recruitment cascade on mouse heart endothelial cells. Arrow points at a T cell transmigrating, and star points at a T cell adhere.
Apply to the Sackler School
The priority application deadlines are as follows:
December 1: Basic Science Division PhD Programs
February 15: Building Diversity in Biomedical Sciences
March 31: Post-Baccalaureate Research Program
May 1: Clinical & Translational Science, MS in Pharmacology & Drug Development
June 15: Online Certificate in Fundamentals of Clinical Care Research