Chapter 315 - Signal Transduction in T Lymphocytes

Abstract

This chapter provides a broad overview of T cell signaling, with emphasis on the signaling molecules and pathways important for antigen-induced signal transduction and elicitation of effector functions. Most mature T cells express αβ T cell receptor (TCR) but some T cells, especially those in mucosal tissues, express γδ TCR. Binding of a peptide-major histocompatibility complex (MHC) to the TCR triggers the recruitment and trans-autocatalytic activation of src family protein tyrosine kinase (PTK), such as p56lck and p59fyn. These src family PTKs rapidly phosphorylate the paired tyrosines within the immunoreceptor tyrosine-based activation motif (ITAMs) of the ζζdimer and the CD3 subunits, thus generating binding sites for the cytosolic syk family PTK ζ chain-associated protein of 70 kDa (ZAP-70), which contains tandem Src homology 2 (SH2) domains. TCR signalosomes consist of transmembrane receptors, protein kinases, phosphatases, and their substrates, all of which are organized into signaling machines by anchoring, adapter, and scaffolding proteins. Signalosomes connect events on the plasma membrane to distal signaling cascades, which ultimately modulate T cell biology. Formation of signalosomes is aided by compartmentalization of the plasma membrane into detergent-insoluble, sphingolipid/cholesterol-enriched microdomains, which promote the recruitment of signal transduction molecules to the TCR signaling machine upon TCR engagement. These areas of the T cell surface are also known as lipid rafts. Palmitoylation constitutively embeds several components, such as Lck and Fyn, into these lipid microdomains, whereas others, such as ZAP-70, relocalize into rafts upon TCR engagement. Co-receptors are associated with the TCR/CD3-ζζ complex upon T cell activation. Their presence in the TCR multi-component signaling machine amplifies or modulates the activation signal.