Limiting T Cell Activation

Science's STKE  10 Feb 2004:
Vol. 2004, Issue 219, pp. tw49
DOI: 10.1126/stke.2192004TW49

Rivas et al. reinvestigated the role of the actin cytoskeleton in T cell activation and discovered evidence for negative modulation of T cell receptor (TCR)-mediated signaling. The formation of an "immunological synapse" between T cells and antigen-presenting cells (APCs) depends on actin polymerization and reorganization of the cytoskeleton, consistent with the notion that the actin cytoskeleton amplifies T cell signaling and promotes T cell activation. Noting recent research that cast doubts on the requirement for the immunological synapse in activation, Rivas et al. examined the effect of pharmacological disruption of the actin cytoskeleton on T cell activation. Although cytochalasin D (CytoD) disrupted the formation of stable T cell-APC conjugates and attenuated proximal TCR signaling, both CytoD and latrunculin B enhanced cytokine production in stimulated Th1 and Th2 CD4+ T cell clones and in CD4+ and CD8+ TCR transgenic T cells. CytoD increased interleukin-2 (IL-2) transcription in Th1 T cells stimulated with antibodies against CD3 and CD28, antigen-loaded APCs, or phorbol myristate acetate plus ionomicin (PMA and I). CytoD inhibited an increase in plasma membrane calcium ATPase produced by stimulation with PMA and I, prolonged the duration of intracellular calcium signals in response to various stimuli, and prolonged the nuclear accumulation of nuclear factor of activated T cells (NFAT, whose nuclear import is sensitive to calcium). Thus, the actin cytoskeleton appears to play multiple roles in T cell activation, including a negative effect on cytokine production mediated through modulation of calcium-NFAT signaling.

F. V. Rivas, J. P. O'Keefe, M.-L. Alegre, T. F. Gajewski, Actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration. Mol. Cell. Biol. 24, 1628-1639 (2004). [Abstract] [Full Text]