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© The Rockefeller University Press, 0021-9525/1998//861 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 861-871

Article

Cytoskeletal Polarization of T Cells Is Regulated by an Immunoreceptor Tyrosine-based Activation Motif–dependent Mechanism



Bente Lowin-Kropf*, Virginia Smith Shapiro*, and Arthur Weiss*,{ddagger},§

* Department of Medicine, {ddagger} Department of Microbiology and Immunology, § Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143

Abstract. Binding of a T cell to an appropriate antigen-presenting cell (APC) induces the rapid reorientation of the T cell cytoskeleton and secretory apparatus towards the cell–cell contact site in a T cell antigen receptor (TCR) and peptide/major histocompatibility complex–dependent process. Such T cell polarization directs the delivery of cytokines and cytotoxic mediators towards the APC and contributes to the highly selective and specific action of effector T cells. To study the signaling pathways that regulate cytoskeletal rearrangements in T lymphocytes, we set up a conjugate formation assay using Jurkat T cells as effectors and cell-sized latex beads coated with various antibodies as artificial APCs. Here, we report that beads coated with antibodies specific for the TCR-CD3 complex were sufficient to induce T cell polarization towards the bead attachment site, as judged by reorientation of the microtubule-organizing center (MTOC) and localized actin polymerization. Thus, these cytoskeletal changes did not depend on activation of additional coreceptors. Moreover, single subunits of the TCR complex, namely TCR-{zeta} and CD3{varepsilon}, were equally effective in inducing cytoskeletal polarization. However, mutagenesis of the immunoreceptor tyrosine-based activation motifs (ITAMs), present three times in TCR-{zeta} and once in CD3{varepsilon}, revealed that the induction of cytoskeletal rearrangements required the presence of at least one intact ITAM. In agreement with this result, lack of functional Lck, the protein tyrosine kinase responsible for ITAM phosphorylation, abolished both MTOC reorientation and polarized actin polymerization. Both inhibitor and transient overexpression studies demonstrated that MTOC reorientation could occur in the absence of Ras activation. Our results suggest that APC-induced T cell polarization is a TCR-mediated event that is coupled to the TCR by the same signaling motif as TCR-induced gene activation, but diverges in its distal signaling requirements.

The authors thank members of the Weiss laboratory for helpful discussions, and in particular Drs. D. Yablonski and N.S.C. van Oers for critical reading of the manuscript. We gratefully acknowledge the technical assistance of T. Laroche and the laser scanning microscope.

This work was supported in part by grants from the Boehringer Ingelheim Fonds (B. Lowin-Kropf) and the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (DRG-1356 to V. Smith Shapiro).

Address all correspondence to Dr. A. Weiss, Howard Hughes Medical Institute, U 426, 3rd and Parnassus Avenues, UCSF, San Francisco, CA 94143-0724. Tel.: (415) 476-1291. Fax: (415) 502-5081.

B. Lowin-Kropf's present address is Ludwig Institute for Cancer Research, Lausanne Branch, 1066 Epalinges, Switzerland.

1. Abbreviations used in this paper: APC, antigen-presenting cell; ERK, extracellular signal-regulated kinase; ITAM, immunoreceptor tyrosine-based activation motif; MAP, microtubule-associated protein; MHC, major histocompatibility complex; MTOC, microtubule-organizing center; PI-3, phosphatidylinositol 3; PTK, protein tyrosine kinase; SH2, src-homology-domain 2; TAg, T antigen; TCR, T cell antigen receptor; ZAP-70, zeta-associated protein 70.


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