Regulatory mechanisms in T cell receptor signalling

Abstract

The remarkable T cell receptor (TCR) performs essential functions in the initiation of intracellular signals required for T cell development, repertoire selection and effector responses to foreign antigens. How TCR signals elicit such diverse cellular responses and outcomes remains a major question for investigation. Recent years have witnessed important advances in our understanding of the regulatory processes that control and modulate the TCR signalling response. Here, we review newly identified mechanisms for the regulation of TCR signalling and then discuss how the TCR signalling response is regulated to control two critical cellular processes - namely, positive selection and T cell homeostasis.

What did we learn from CTLA‐4 insufficiency on the human immune system?

“…Following the engagement of the major histocompatibility complex (MHC) with the TCR, sufficient T cell activation requires additional costimulatory signals . CD28 effectively functions as a costimulatory molecule . While CD28 is constitutively expressed on T cells, CTLA‐4 is mainly localized in the intracellular compartment and is rapidly upregulated following strong TCR signaling .…”

“…After the interaction between T cells and APCs and the engagement of costimulatory signals, CD4 and CD8 bind to LCK, leading to the phosphorylation of immunoreceptor tyrosine‐based activation motifs (ITAMs) in the CD3 subunits . Its phosphorylation recruits ζ‐chain‐associated protein kinase of 70 kDa (ZAP70) and promotes the Lck‐mediated activation of ZAP70 .…”

“…Linker for activation of T cells (LAT), phosphorylated by ZAP70, generates docking sites for other adapter molecules, including growth factor receptor‐bound protein 2 (GRB2), SH2‐domain‐containing leukocyte protein of 76 kDa (SLP76), phospholipase C (PLC) γ1, inducible T cell kinase (ITK), and vav guanine nucleotide exchange factor 1 (VAV1), resulting in the formation of a LAT signalosome. Subsequently, the signalosome activates the TCR downstream signaling by inducing cytoskeletal remodeling, an increase in intracellular calcium, and the activation of mitogen‐activated protein (MAP) kinase, protein kinase C (PKC), and calcineurin . The TCR downstream signaling enhances the nuclear translocation of key transcriptional factors for T cell activation, such as nuclear factor of activated T cells (NFAT), JUN via Jun N‐terminal kinase (JNK), activator protein 1 (AP‐1) via extracellular signal‐regulated kinase (ERK), nuclear factor (NF)‐κB via BCL‐10, CADR‐containing MAGUK protein 1 (CARMA1), and mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) .…”

“…Subsequently, the signalosome activates the TCR downstream signaling by inducing cytoskeletal remodeling, an increase in intracellular calcium, and the activation of mitogen‐activated protein (MAP) kinase, protein kinase C (PKC), and calcineurin . The TCR downstream signaling enhances the nuclear translocation of key transcriptional factors for T cell activation, such as nuclear factor of activated T cells (NFAT), JUN via Jun N‐terminal kinase (JNK), activator protein 1 (AP‐1) via extracellular signal‐regulated kinase (ERK), nuclear factor (NF)‐κB via BCL‐10, CADR‐containing MAGUK protein 1 (CARMA1), and mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) . The signaling pathway through phosphatidylinositol 4,5‐bisphosphatase 3‐kinase (PI3K) promotes phosphorylation of RACα serine/threonine‐protein kinase (AKT) by phosphatidylinositol (3,4,5)‐trisphosphate (PIP3), leading to T cell proliferation through S6 kinase β1 .…”

“…The signaling pathway through phosphatidylinositol 4,5‐bisphosphatase 3‐kinase (PI3K) promotes phosphorylation of RACα serine/threonine‐protein kinase (AKT) by phosphatidylinositol (3,4,5)‐trisphosphate (PIP3), leading to T cell proliferation through S6 kinase β1 . On the other hand, several protein phosphatases, including CD45, Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1), SHP‐2, and protein tyrosine phosphatase nonreceptor type (PTPN) 22, induce TCR inhibitory signals . For example, CD45 dephosphorylates LCK, and SHP‐1 and PTPN22 are also thought to dephosphorylate LCK and ZAP70 .…”