Cytotoxic immunological synapses

Abstract

One of the most fundamental activities of the adaptive immune system is to kill infected cells and tumor cells. Two distinct pathways mediate this process, both of which are facilitated by a cytotoxic immunological synapse. While traditionally thought of as innate immune cells, natural killer (NK) cells are now appreciated to have the capacity for long-term adaptation to chemical and viral insults. These cells integrate multiple positive and negative signals through NK cell cytotoxic or inhibitory synapses. The traditional CD8(+)alphabeta T-cell receptor-positive cells are among the best models for the concept of an immunological synapse, in which vectoral signaling is linked to directed secretion in a stable interface to induce apoptotic cell death in an infected cell. Large-scale molecular organization in synapses generated a number of hypotheses. Studies in the past 5 years have started to provide clear answers regarding the validity of these models. In vivo imaging approaches have provided some hints as to the physiologic relevance of these processes with great promise for the future. This review provides an overview of work on cytotoxic immunological synapses and suggests pathways forward in applying this information to the development of therapeutic agents.

Fig. 1. Schematic of CTL synapse and kinapse

(A). CTL synapse. Strong TCR signal and CD8. The key feature is the symmetric actin pattern with centripetal flow (white arrows). This forms the pSMAC (red, ICAM-1) and positions the TCR for Tsg101 dependent movement in the cSMAC (green, TCR). In this efficient system the granules (purple) are targeted to the MTOC along microbutules (heavy black lines) prior to movement of the MTOC and Golgi to the cSMAC secretory domain. Some of the cSMAC-associated TCR is in multivesicular bodies (blue with green dots). (B). CTL kinapse. Weak TCR signal or CD4. The key feature is a asymmetric actin pattern with net retrograde actin flow (white arrow) inducing forward motion of the cell (black arrow). This forms the asymmetric focal zone (red, ICAM-1), whereas TCR microclusters do not accumulate in a cSMAC. The MTOC moves to the actin-depleted secretory domain, but the granules reach the domain more slowly. (C). Relative efficiency of the two configurations. The presence of an intact cSMAC gains ~6× increase in killing efficiency. The tight granule packing around the MTOC results in a ~30× increase in killing efficiency compared to the loose granule distribution.