Red light-green light: T-cell trafficking in cardiac and vascular inflammation

Abstract

Extravasation of T cells from the bloodstream into inflamed tissues requires interactions between T cells and vascular endothelial cells, a necessary step that allows T cells to exert their effector function during the immune response to pathogens and to sterile insults. This cellular cross talk involves adhesion molecules on both the vascular endothelium and the T cells themselves that function as receptor-ligand pairs to slow down circulating T cells. These will eventually extravasate into sites of inflammation when they receive the correct chemokine signals. Accumulation of T cells within the vascular wall can lead to vessel thickening and vascular disease, whereas T-cell extravasation into the myocardium often leads to cardiac chronic inflammation and adverse cardiac remodeling, hallmarks of heart failure. On the flip side, T-cell trafficking is required for pathogen clearance and to promote tissue repair after injury resulting from cardiac ischemia. Thus, a better understanding of the central players mediating these interactions may help develop novel therapeutics to modulate vascular and cardiac inflammation. Here, we review the most recent literature on pathways that regulate T-cell transendothelial migration, the last step leading to T-cell infiltration into tissues and organs in the context of vascular and cardiac inflammation. We discuss new potential avenues to therapeutically modulate these pathways to enhance or prevent immune cell infiltration in cardiovascular disease.

Keywords: cardiovascular; inflammation; leukocytes; pathophysiology; trafficking.

Graphical abstract

Figure 1.

A: classic players of TEM involve T-cell selectin ligands and integrins, which interact with EC selectins and ICAM-1 and VCAM-1, respectively. VE-Cad is at the cell junctions and modulates leukocyte passage across ECs (3). Endothelial cell STING controls Type I-IFN production, which signals through IFNAR and induces CXCL10, attracting CXCR3⁺ T cells (7). TRPC6 colocalizes with PECAM-1 on the surface of ECs (8) and enables an influx of cytosolic calcium that activates Calmodulin (CaM) and CAMKIIδ for leukocyte TEM (9). Mechanosensing activates EC-PIEZO-1 for subsequent leukocyte TEM (10), and macrophage and T-cell miR-34a-5p represses CXCL10 and CXCL11 mRNA and decreases CXCR3, potentially impairing TEM (11). B: in hypertension, T-cell-derived miR-214 induces proinflammatory gene expression and endothelial dysfunction (12). Activated by IgE, Nhe1 activity controls macrophage accumulation and EC adhesion molecule expression (13). Human CD16⁺CX3CR1⁺ monocytes interact with and induce the production of EC-derived CX3CL1 (14). C: activated CXCR3⁺ T cells recognize CXCL9/10 to traffic to the heart (15). Failing human hearts have decreased cardiomyocyte T-cad expression (16), increased cardiomyocyte CAMKIIδ and NLRP3 inflammasome activation that results in leukocyte myocardial infiltration (17). IL-3⁺CD4⁺ T cells stimulate IL-3R⁺ macrophages to produce monocyte attracting chemokines, and recruited monocytes differentiate into APCs that stimulate IL-3⁺CD4⁺ T-cell proliferation (18). D: global CCL17 deletion increases Treg recruitment post-MI (19), and cardiomyocyte GRK5 increases monocyte recruitment post-MI, with no effect on T-cell recruitment (20). Image created with BioRender.com and published with permission. ECs, endothelial cells; TEM, transendothelial migration; Treg, T regulatory cell.