Adhesion to laminin-1 and collagen IV induces the formation of Ca 2+ microdomains that sensitize mouse T cells for activation

• Published in: Science signaling Vol. 16; no. 790; p. eabn9405
• Main Authors: Weiß, Mariella, Hernandez, Lola C, Gil Montoya, Diana C, Löhndorf, Anke, Krüger, Aileen, Kopdag, Miriam, Uebler, Liana, Landwehr, Marie, Nawrocki, Mikolaj, Huber, Samuel, Woelk, Lena-Marie, Werner, René, Failla, Antonio V, Flügel, Alexander, Dupont, Geneviève, Guse, Andreas H, Diercks, Björn-Philipp
• Format: Journal Article
• Language: English
• Published: United States 20-06-2023
• Subjects: Animals; Collagen - metabolism; Endothelial Cells; Extracellular Matrix Proteins - metabolism; Mice; Receptors, Antigen, T-Cell - metabolism; T-Lymphocytes - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.abn9405

During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca
microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca
microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP
R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca
microdomains required the concerted activity of two to six IP
Rs and ORAI1 channels to achieve the increase in the Ca
concentration in the ER-plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca
microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca
response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca
microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.