Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.916137
Keywords
T cells; L-plastin; immune synapse formation; immune cell adhesion and migration; mechanotransduction; LFA-1 (CD11A/CD18/ITGAL/ITGB2); F-actin assembly; cytoskeleton
Categories
Funding
- National Institutes of Health [R01-AI104732, R21EB030171, R01 AI118719, HL148033, R01AI139540, R56 AI104732]
- National Science Foundation [CBET-1900277, CMMI1548571]
- American Lung Association [ETRA 736343]
- Washington University in Saint Louis Children's Discovery Institute [CDI-CORE-2019-813, CDI-CORE-2015-505]
- Foundation for Barnes-Jewish Hospital grants [3770, 4642]
- American Association of Immunologists AAI Careers in immunology fellowship
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This article summarizes how the actin-bundling protein L-plastin (LPL) regulates T-cell activation and migration. LPL enhances actin polymerization and promotes intercellular adhesion and immune synapse formation. LPL plays important roles in T-cell migration, activation, and cytokine production and proliferation.
Rapid re-organization of the actin cytoskeleton supports T-cell trafficking towards immune sites and interaction with antigen presenting cells (APCs). F-actin rearrangement enables T-cell trafficking by stabilizing adhesion to vascular endothelial cells and promoting transendothelial migration. T-cell/APC immune synapse (IS) maturation also relies upon f-actin-anchored LFA-1:ICAM-1 ligation. Therefore, efficient T-cell responses require tight regulation of f-actin dynamics. In this review, we summarize how the actin-bundling protein L-plastin (LPL) regulates T-cell activation and migration. LPL enhances f-actin polymerization and also directly binds to the beta 2 chain of the integrin LFA-1 to support intercellular adhesion and IS formation in human and murine T cells. LPL- deficient T cells migrate slowly in response to chemo-attractants such as CXCL12, CCL19, and poorly polarize towards ICAM-1. Loss of LPL impairs thymic egress and intranodal motility. LPL is also required for T-cell IS maturation with APCs, and therefore for efficient cytokine production and proliferation. LPL-/- mice are less susceptible to T-cell mediated pathologies, such as allograft rejection and experimental autoimmune encephalomyelitis (EAE). LPL activity is regulated by its N-terminal headpiece , which contains serine and threonine phosphorylation and calcium- and calmodulin-binding sites. LPL phosphorylation is required for lamellipodia formation during adhesion and migration, and also for LFA-1 clustering during IS formation. However, the precise molecular interactions by which LPL supports T-cell functional responses remain unclear. Future studies elucidating LPL-mediated regulation of T-cell migration and/or activation may illuminate pathways for therapeutic targeting in T-cell-mediated diseases.
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