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

beta(1)-integrins expressed on resting T cells support only minimal ad hesion to integrin ligands, T cell activation through multiple stimuli , including phorbol ester treatment and Ab cross-linking of the CD3/TC R complex, results in a rapid and transient switch in integrin functio n from low to high avidity binding, The exact nature of the intracellu lar 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 be ta(1)-integrin function on T cells, We isolated mutants of the Jurkat T cell line that express beta(1)- and beta(2)-integrins but do not exh ibit 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 p rotein kinase ERK1 and an inability to produce IL-2, Another mutant wi th defective integrin function has IL-2 production intact, Complementa tion 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 re agents for the identification of integrin regulatory factors and indic ate possible sites of pharmacologic intervention that could prevent in tegrin-dependent migration and localization in the process of inflamma tion, while leaving other T cell functions intact.