ALPHA(4)BETA(1) (CD49D CD29) INTEGRIN COSTIMULATION OF HUMAN T-CELLS ENHANCES TRANSCRIPTION FACTOR AND CYTOKINE INDUCTION IN THE ABSENCE OFALTERED SENSITIVITY TO ANTI-CD3 STIMULATION/

The integrin alpha(4) beta(1) can provide a costimulus to induce IL-2 secretion and IL-2R expression leading to enhanced proliferation of pu rified, peripheral blood T cells. Similar to expression of IL-2, we de monstrated that recombinant vascular-cell adhesion molecule-1, when co -immobilized with anti-CD3 mAb, significantly enhanced the induction o f transcription factors NF-AT, AP-1, and NF-kappa B as determined by e lectromobility shift assays. alpha(4) beta(1) ligation alone had no ef fect on transcription factor binding. The requirements for induction o f transcription factors reflected the requirements for the secretion o f multiple cytokines, including IL-2, TNF-alpha, IFN-gamma, and granul ocyte macrophage-CSF. In contrast to freshly isolated T cells, in vitr o-cultured T cells did not require costimulation for cytokine secretio n in response to anti-CD3 alone. Comparison of the dose response to an ti-CD3 stimulation demonstrated that half-maximal induction of IL-2 wa s achieved using the same dose of anti-CD3 for both freshly isolated a nd cultured T cells. Furthermore, the dose of OKT3 required to achieve half-maximal activation was the same using PMA or different concentra tions of alpha(4) beta(1) ligands. Therefore, costimulation by alpha(4 ) beta(1) ligands was not due to stabilization of the interaction of t he cells with its substrate. We conclude, rather, that alpha(4) beta(1 ) in freshly isolated T cells delivers a distinct signal that synergiz es early with signals initiated by TCR/CD3 ligation to induce DNA bind ing of multiple transcription factors required for cytokine gene induc tion.