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Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation
S G Irving1, C H June, P F Zipfel
1Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
The delivery of a mitogenic signal to T cells via any one of several cell surface molecules elicits a variety of intracellular responses, some or all of which regulate subsequent gene expression events. The expression of nine novel mitogen-induced genes in response to various T-cell-activating agents was examined to evaluate the diversity of pathways which regulate such genes. The relative contribution of distinct secondary signals, individually or together, to mitogen-stimulated gene induction and the capability of individual genes to respond to the sometimes divergent signals generated from different cell surface structures is addressed. The activation of T cells with mitogenic monoclonal antibodies directed against the CD2 or CD3 cell surface molecules, or with phytohemagglutinin, induced all nine genes. Thus, stimulation by fully mitogenic agents regardless of cell surface-binding specificity correlated with the expression of all of the genes studied. However, heterogeneous patterns of gene expression, encompassing five regulatory classes, were revealed by the use of phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 monoclonal antibody, agents which mediated only a subset of intracellular events and thus an incomplete mitogenic signal. Interleukin-2 and two novel lymphokines represented one regulatory class that appeared to require unique transcriptional activation signals relative to the other mitogen-induced genes. As demonstrated in the accompanying paper (P. F. Zipfel, S. G. Irving, K. Kelly, and U. Siebenlist, Mol. Cell. Biol. 9:1041-1048, 1989), the immediate transcriptional response of T cells to mitogenic stimulation is quite complex, involving numerous genes beyond those which have been previously described. Furthermore, the discrimination of several regulatory phenotypes among these nine genes suggests that a multiplicity of signaling pathways extends from the cell surface to the level of transcription.
Insights
T-cell activation by different agents reveals diverse gene expression patterns. Fully mitogenic signals induce all nine genes, while partial signals create distinct regulatory classes, indicating complex signaling pathways from cell surface to gene transcription.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- T-cell activation involves intracellular responses regulating gene expression.
- Understanding the diversity of T-cell signaling pathways is crucial for deciphering immune responses.
Purpose of the Study:
- To investigate the expression of nine novel mitogen-induced genes in T cells.
- To evaluate the diversity of regulatory pathways controlling gene expression in response to T-cell activation.
- To determine how different T-cell surface molecules and signaling agents influence gene induction patterns.
Main Methods:
- T cells were activated using various agents: mitogenic monoclonal antibodies (anti-CD2, anti-CD3), phytohemagglutinin, phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 antibody.
- Gene expression patterns of nine novel mitogen-induced genes were analyzed in response to these stimuli.
Main Results:
- Fully mitogenic agents (anti-CD2, anti-CD3, phytohemagglutinin) induced the expression of all nine genes.
- Partial mitogenic agents (phorbol 12-myristate 13-acetate, calcium ionophore, anti-CD28) resulted in heterogeneous gene expression patterns, categorized into five regulatory classes.
- Interleukin-2 and two novel lymphokines formed a distinct regulatory class requiring unique transcriptional signals.
Conclusions:
- T-cell activation by distinct surface molecules and signaling pathways leads to complex and diverse gene expression profiles.
- Multiple signaling pathways from the cell surface converge at the transcriptional level, regulating specific sets of genes.
- The findings highlight the intricate nature of T-cell immediate transcriptional responses to mitogenic stimulation.