Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond

Abstract

Cytoskeletal polarization is crucial for many aspects of immune function, ranging from neutrophil migration to the sampling of gut flora by intestinal dendritic cells. It also plays a key role during lymphocyte cell-cell interactions, the most conspicuous of which is perhaps the immunological synapse (IS) formed between a T cell and an antigen-presenting cell (APC). IS formation is associated with the reorientation of the T cell's microtubule-organizing center (MTOC) to a position just beneath the cell-cell interface. This cytoskeletal remodeling event aligns secretory organelles inside the T cell with the IS, enabling the directional release of cytokines and cytolytic factors toward the APC. MTOC polarization is therefore crucial for maintaining the specificity of a T cell's secretory and cytotoxic responses. It has been known for some time that T cell receptor (TCR) stimulation activates the MTOC polarization response. It has been difficult, however, to identify the machinery that couples early TCR signaling to cytoskeletal remodeling. Over the past few years, considerable progress has been made in this area. This review will present an overview of recent advances, touching on both the mechanisms that drive MTOC polarization and the effector responses that require it. Particular attention will be paid to both novel and atypical members of the protein kinase C family, which are now known to play important roles in both the establishment and the maintenance of the polarized state.

Keywords: T cell; cell polarity; cytoskeleton; lymphocyte; protein kinase C; signal transduction.

FIGURE 1

Schematic diagram showing the transition between migratory and synaptic polarity that occurs upon antigen recognition by T cells. In general, the entire process takes 2–3 min. The APC is shown as a gray semicircle.

FIGURE 2

Schematic diagram showing the distribution of polarity complexes in synaptic T cells 30 min (top), and 12 h (bottom) after antigen recognition. The cell at 12 h is depicted as undergoing mitosis. The APC is shown as a gray semicircle.

FIGURE 3

chematic diagram depicting the effects of synaptic secretory responses. (A) Weak cytokine secretion affects only the APC and cells in its immediate vicinity. (B) Strong cytokine secretion affects a larger number of bystander cells. (C) Cytolytic killing, mediated by perforin and granzyme, is restricted to the APC. The scope of cytokine diffusion is denoted in orange. T cells are colored blue, with the MTOC and microtubules in black. Bystander cells are depicted as gray squares. Adapted from Sanderson et al. (2012).