The Pilar Alcaide Lab
Why do we study T lymphocytes?
T cell recruitment into organs and tissues is a hallmark of several chronic inflammatory processes. Among the different T cells subsets, T helper type 17 (Th17) and Th1 cells play a major role in autoimmunity and chronic inflammation, whereas others such as T regulatory (Treg) cells, suppress Th cells effector function and vascular endothelial activation. We have demonstrated that different T cell subsets differ in their ability to interact with the activated vascular endothelium to traffic into certain tissues. The lab works in the identification of functional T cell specific subset adhesion molecules and the mechanisms regulating vascular endothelial cell adhesion and transmigration. One of the molecules we have identified to function differently among effector Th cell subsets is syalomucin CD43, and our efforts are geared to understand why, as well as its role in Treg cell trafficking during antigen dependent and independent inflammation in vivo, and the mechanisms regulating its function using flow chamber and videomicroscopy studies in vitro.
Figure 1: A. Real time videomicroscopy set up to study T cell interactions with the vascular endothelium under physiological flow conditions in vitro. B. Differential interference contrast (DIC) microscopy imaging of Th17 cells (green) and Th1 cells (red) interactions with mouse heart endothelial cells stimulated 4-hr with TNFα under conditions of shear stress (1 dyne/cm2). C. Scheme representing CD43 mediated interactions with the vascular endothelium in T cell subsets, obtained with this approach from data generated using this approach and T cells from wild type and CD43-/- mice.
Why do we study heart failure?
The progressive syndrome of Heart Failure (HF), a leading cause of mortality and hospitalizations, 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 adverse cardiac remodeling. Our lab studies the role of adaptive immunity mediated inflammation in regulating adverse cardiac remodeling and HF. The lab uses a well established experimental mouse model of HF, and a variety of T cell, adhesion molecule and chemokine receptor deficient and reporter mice. We study the mechanisms of T cell activation, the mechanisms regulating T cell trafficking to the heart, and the T cell actions on cardiac resident cells that result in cardiac hypertrophy, cardiac fibrosis, and HF. In collaboration with cardiologists, the lab also studies the role of T cells in human non-ischemic HF.
Figure 2: Model of the role of adaptive immunity in non-ischemic HF. Our lab has demonstrated that in response to high left ventricular pressure (LVP), CD4+ T cells are activated by dendritic cells (DC) specifically in the lymph nodes that drain the heart, are recruited to the heart by interacting with adhesion molecules and chemokines presented by the endothelial cells (EC), when they induce contact dependent cardiac fibrosis upon interactions with cardiac fibroblasts (CFB) and impair cardiac function. We combine in vitro and in vivo studies to understand this process in depth and how specific pathways may be targeted therapeutically. The novel gut-heart axis is also an area of investigation in our lab.
T cell activation in the gut-heart axis
The gut is the highest reservoir of T cells and the home of commensal bacteria. Recent studies in our lab focus on understanding the role of gut dysbiosis in T cell activation and its implications in the progression of heart failure.
Figure 3: A. T cells are found infiltrated in the human failing heart. Immunohistochemistry for CD3+ T cells in human heart ventricular tissue. Arrows indicate representative T cells in the heart of a HF patient who underwent Left ventricular assisted device (LVAD) placement. Control heart was obtained from NDRI. B. T cells activated in response to TAC adhere and transmigrate across mouse heart endothelial cells. Example of CD4+ T cells isolated from cardiac draining lymph nodes of mice 4 weeks after TAC adhering (indicated with a *) and transmigrating (indicated with an arrow) across 4h TNFα activated mouse heart endothelial cells under shear flow conditions in vitro. C. T cell deficient mice (TCRα-/-) do not develop cardiac fibrosis in response to TAC. Picrosirius red staining of heart sections from Sham and TAC WT and TCRα-/- mice indicating absence of collagen deposition (in pink) in the absence of T cells. D. T cell contact dependent cardiac fibrosis. T cell (green) contact with cardiac fibroblasts induces αSMA expression (shown in red) and transformation to pro-fibrotic myofibroblasts. E. TCRα-/- are protected from TAC induced HF. M mode Echocardiography images show preserved systolic function in TCRα-/- mice in response to TAC as compared to WT TAC mice. Scale bar is indicated in red.