Isolation and characterization of cell lines with genetically distinct mutations downstream of protein kinase C that result in defective activation-dependent regulation of T cell integrin function

James L. Mobley, Elizabeth Ennis, Yoji Shimizu

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

β1-integrins expressed on resting T cells support only minimal adhesion to integrin ligands. T cell activation through multiple stimuli, including phorbol ester treatment and Ab cross-linking of the CD3/TCR complex, results in a rapid and transient switch in integrin function from low to high avidity binding. The exact nature of the intracellular signals involved in this avidity switch remain poorly defined, but the ability of phorbol esters to induce such up-regulation implicates a role for protein kinase C (PKC). We have used a genetic approach to identify factors other than PKC that regulate activation-dependent β1-integrin function on T cells. We isolated mutants of the Jurkat T cell line that express β1- and β2-integrins but do not exhibit increased integrin activity in response to PMA stimulation or CD3 cross-linking. PKC activity appears to be normal in the mutants. One mutation is associated with an altered form of the mitogen-activated protein kinase ERK1 and an inability to produce IL-2. Another mutant with defective integrin function has IL-2 production intact. Complementation analysis verified that these two types of mutants are genetically distinct. Thus, two mutations downstream of PKC have been identified that alter the process of integrin regulation without affecting T cell viability or proliferative capacity. These mutants represent novel reagents for the identification of integrin regulatory factors and indicate possible sites of pharmacologic intervention that could prevent integrin-dependent migration and localization in the process of inflammation, while leaving other T cell functions intact.

Original languageEnglish (US)
Pages (from-to)948-956
Number of pages9
JournalJournal of Immunology
Volume156
Issue number3
StatePublished - Feb 1 1996

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