Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered 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 purified, peripheral blood T cells. Similar to expression of IL-2, we demonstrated that recombinant vascular-cell adhesion molecule-1, when co-immobilized with anti-CD3 mAb, significantly enhanced the induction of transcription factors NF-AT, AP-1, and NF-kappa B as determined by electromobility shift assays. alpha 4 beta 1 ligation alone had no effect on transcription factor binding. The requirements for induction of transcription factors reflected the requirements for the secretion of multiple cytokines, including IL-2, TNF-alpha, IFN-gamma, and granulocyte macrophage-CSF. In contrast to freshly isolated T cells, in vitro-cultured T cells did not require costimulation for cytokine secretion in response to anti-CD3 alone. Comparison of the dose response to anti-CD3 stimulation demonstrated that half-maximal induction of IL-2 was achieved using the same dose of anti-CD3 for both freshly isolated and cultured T cells. Furthermore, the dose of OKT3 required to achieve half-maximal activation was the same using PMA or different concentrations of alpha 4 beta 1 ligands. Therefore, costimulation by alpha 4 beta 1 ligands was not due to stabilization of the interaction of the cells with its substrate. We conclude, rather, that alpha 4 beta 1 in freshly isolated T cells delivers a distinct signal that synergizes early with signals initiated by TCR/CD3 ligation to induce DNA binding of multiple transcription factors required for cytokine gene induction.
Udagawa
T
T
Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Woodside
D G
DG
McIntyre
B W
BW
D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000494:pharmacology*; D016023:Integrins / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016853:Muromonab-CD3 / Q000494:pharmacology; D016328:NF-kappa B / Q000096:biosynthesis; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology
D017252:CD3 Complex; D016207:Cytokines; D004268:DNA-Binding Proteins; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D016853:Muromonab-CD3; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1