News and Publications

Regulation of T-Cell Adhesion and Signal Transduction

A.M. O'Rourke, P. Filipowicz, A. Radke, G. Weitz*

* Novartis Pharma, Basel, Switzerland

The interaction between a T lymphocyte and an antigen-presenting cell involves a complex sequence of adhesion and signaling events that culminate in lymphocyte activation. The specificity of the cell interaction is dictated by the antigen-specific T-cell receptor, but several members of the integrin family of adhesion molecules also contribute to cell adhesion and signal transduction. Our research is aimed at understanding how T cells regulate the adhesion and signaling functions of the integrins. However, the highly multivalent nature of the interaction between a T cell and an antigen-presenting cell makes it difficult to pinpoint contributions from individual receptors. For this reason, we use a model system in which purified integrin ligands are immobilized in planar membranes, thus allowing T-cell adhesion and signaling events elicited by the receptors to be examined in isolation.

In the past year, we continued our study of the function of T-cell integrins, in particular, the intracellular events that regulate their adhesive function. Although many external factors act on T cells to increase the avidity of integrins, the biochemical events that control increased binding remain unclear. One focus of our work is determining the function of a mouse homolog of the human cytohesin-1 protein. This cytoplasmic protein is thought to play a critical regulatory role in the binding of lymphocyte function--associated antigen 1 to intracellular adhesion molecule 1, and in the coming year we plan to determine its role in mouse T-cell adhesion. A second focus of our research is determining intracellular pathways that may link occupancy of T-cell receptors to increased integrin adhesion. Recent results indicated that interplay between calcium-activated proteases and the actin-based cytoskeleton may be involved in allowing adhesion mediated by activation of T-cell receptors.

In collaboration with J. Kaye, Department of Immunology, we have obtained novel evidence that components of the p21ras/MAPK intracellular signaling pathway play a positive role in lymphocyte adhesion through binding of lymphocyte function--associated antigen 1 to intracellular adhesion molecule 1. Finally, we have continued our study of integrin function in T cells from aged mice. The decline in function of the immune system that accompanies aging may reflect impaired function of memory T cells. We detected a number of changes in the expression and function of several T-cell integrins in mice of advanced age, and in the coming year, we will test the hypothesis that such changes markedly affect the ability of T cells to respond to antigen-presenting cells.

PUBLICATIONS

O'Rourke, A.M., Escuro, G., Feeney, A.J. Cloning and sequencing of cDNA encoding mouse cytohesin-1. Immunogenetics, in press.

O'Rourke, A.M., Webb, S.R. Crosstalk between T and B cells generates B antigen-presenting cells able to induce inositol phosphate production in T cells responding to Mls^a superantigens. Eur. J. Immunol. 27:3253, 1997.