Differential role of ICAM ligands in determination of human memory T cell differentiation.
BACKGROUND
Leukocyte Function Antigen-1 (LFA-1) is a primary adhesion molecule that plays important roles in T cell activation, leukocyte recirculation, and trans-endothelial migration. By applying a multivariate intracellular phospho-proteomic analysis, we demonstrate that LFA-1 differentially activates signaling molecules.


RESULTS
Signal intensity was dependent on both ICAM ligand and LFA-1 concentration. In the presence of CD3 and CD28 stimulation, ICAM-2 and ICAM-3 decreased TGFbeta1 production more than ICAM-1. In long-term differentiation experiments, stimulation with ICAM-3, CD3, and CD28 generated IFNgamma producing CD4+CD45RO+CD62L-CD11aBrightCD27- cells that had increased expression of intracellular BCL2, displayed distinct chemokine receptor profiles, and exhibited distinct migratory characteristics. Only CD3/CD28 with ICAM-3 generated CD4+CD45RO+CD62L-CD11aBrightCD27- cells that were functionally responsive to chemotaxis and exhibited higher frequencies of cells that signaled to JNK and ERK1/2 upon stimulation with MIP3alpha. Furthermore, these reports identify that the LFA-1 receptor, when presented with multiple ligands, can result in distinct T cell differentiation states and suggest that the combinatorial integration of ICAM ligand interactions with LFA-1 have functional consequences for T cell biology.


CONCLUSIONS
Thus, the ICAM ligands, differentially modulate LFA-1 signaling in T cells and potentiate the development of memory human T cells in vitro. These findings are of importance in a mechanistic understanding of memory cell differentiation and ex vivo generation of memory cell subsets for therapeutic applications.
Perez
Omar D
OD
The Baxter Laboratory for Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305, USA. Omar.Perez@nodalityinc.com
Mitchell
Dennis
D
Nolan
Garry P
GP
D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D018106:CD28 Antigens; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D017493:Leukocyte Common Antigens; D053148:Caspase 3