Immunological synapse: a multi-protein signalling cellular apparatus for controlling gene expression

Abstract

The interaction of T cells with antigen-presenting cells is the hallmark of adaptive immunity. In vitro studies have described the formation of an immunological synapse between these cells, and intra-vital imaging has described in great detail the dynamics of these interactions. The immunological synapse has become a paradigm to study signals exchanged between the two cells. A wealth of information has been amassed regarding the localization of signalling molecules, their kinetics and the transcription factors they activate. We continue to discover mechanisms that cause receptors and signalling molecules to compartmentalize in the cell; however, the emerging challenge lies in understanding how the immunological synapse contributes to differentiation. Here, we review some of the transcription factors activated downstream of T-cell receptor signalling and discuss mechanisms by which antigen dose and affinity may influence differentiation. Antigen affinity might change the kind of transcription factors that are activated whereas antigen dose is likely to influence the temporal dynamics of the transcription factors. The immunological synapse is therefore likely to influence differentiation by modulating the trafficking of transcription factors and by promoting asymmetric cell division, an emerging concept.

Figure 1

Schematic representation of T-cell activation, proximal signalling complex and activation of transcription factors. Current model of signalling in T cells states that stimulation of T-cell receptor (TCR) with specific major histocompatibility complex–peptide complexes (MHC-p) leads to phosphorylation of tyrosine residues within the immune receptor tyrosine-based activation motifs (ITAMs) of the invariant CD3 chains by Src family tyrosine kinases (Lck and Fyn). This TCR triggering causes the formation of the multimolecular proximal signalling complex (PSC). Signalling at the PSC causes calcium signals, activation of the Ras–mitogen-activated protein kinase (MAPK) pathway and protein kinase C-θ-dependent formation of the Carma1-BCL10-MALT1 (CBM) complex. These signals activate nuclear factor of activated T cells (NFAT), activating protein 1 (AP-1) and nuclear factor-κB (NF-κB) transcription factors respectively.